Method for controlling particular insect pests by applying anthranilamide compounds

ABSTRACT

This invention pertains to a method for controlling lepidopteran, homopteran, hemipteran, thysanopteran and coleopteran insect pests comprising contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, its N-oxide or an agriculturally suitable salt thereof 
     
       
         
         
             
             
         
       
     
     wherein A and B and R 1  through R 8  are as defined in the disclosure. 
     This invention further relates to a bezoxazinone compound of Formula 10 
     
       
         
         
             
             
         
       
     
     wherein R 4  through R 8  are as defined in the disclosure, useful for preparation of a compound of Formula I.

BACKGROUND OF THE INVENTION

This invention relates to a method of use for controlling invertebrate pests in both agronomic and nonagronomic environments of certain anthranilamides, their N-oxides, agriculturally suitable salts and compositions.

The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different modes of action.

NL 9202078 discloses N-acyl anthranilic acid derivatives of Formula i as insecticides

-   -   wherein, inter alia,     -   X is a direct bond;     -   Y is H or C₁-C₆ alkyl;     -   Z is NH₂, NH(C₁-C₃ alkyl) or N(C₁-C₃ alkyl)₂; and     -   R¹ through R⁹ are independently H, halogen, C₁-C₆ alkyl, phenyl,         hydroxy, C₁-C₆ alkoxy or C₁-C₇ acyloxy.

SUMMARY OF THE INVENTION

This invention pertains to a method for controlling lepidopteran, homopteran, hemipteran, thysanopteran and coleopteran insect pests comprising contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, its N-oxide or an agriculturally suitable salt thereof

wherein

-   -   A and B are independently O or S;     -   R¹ is H, C₁-C₆ alkyl, C₂-C₆ alkoxycarbonyl or C₂-C₆         alkylcarbonyl;     -   R² is H or C₁-C₆ alkyl;     -   R³ is H; C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₆         cycloalkyl, each optionally substituted with one or more         substituents selected from the group consisting of halogen, CN,         NO₂, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄         alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₂-C₆         alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆ trialkylsilyl,         phenyl, phenoxy, 5-membered heteroaromatic rings, and 6-membered         heteroaromatic rings; each phenyl, phenoxy, 5-membered         heteroaromatic ring, and 6-membered heteroaromatic ring         optionally substituted with one to three substituents         independently selected from the group consisting of C₁-C₄ alkyl,         C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl,         C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl,         halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄         alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄         alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈         (alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆         alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈         dialkylaminocarbonyl and C₃-C₆ trialkylsilyl; C₁-C₄ alkoxy;         C₁-C₄ alkylamino; C₂-C₈ dialkylamino; C₃-C₆ cycloalkylamino;         C₂-C₆ alkoxycarbonyl or C₂-C₆ alkylcarbonyl;     -   R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, C₁-C₆ haloalkyl, CN, halogen, C₁-C₄ alkoxy, C₁-C₄         haloalkoxy or NO₂;     -   R⁵ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxyalkyl, C₁-C₄         hydroxyalkyl, C(O)R¹⁰, CO₂R¹⁰, C(O)NR¹⁰R¹¹, halogen, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, NR¹⁰R¹¹, N(R¹¹)C(O)R¹⁰, N(R¹¹)CO₂R¹⁰         or S(O)_(n)R¹²;     -   R⁶ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, CN, C₁-C₄ alkoxy         or C₁-C₄ haloalkoxy;     -   R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆         cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆         haloalkynyl or C₃-C₆ halocycloalkyl; or     -   R⁷ is a phenyl ring, a benzyl ring, a 5- or 6-membered         heteroaromatic ring, a naphthyl ring system or an aromatic 8-,         9- or 10-membered fused heterobicyclic ring system, each ring or         ring system optionally substituted with one to three         substituents independently selected from R⁹;     -   R⁸ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, C₁-C₄ alkoxy or         C₁-C₄ haloalkoxy;     -   each R⁹ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄         alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,         C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,         C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆         cycloalkylamino, C₄-C₈ (allyl)(cycloalkyl)amino, C₂-C₄         alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,         C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;     -   R¹⁰ is H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;     -   R¹¹ is H or C₁-C₄ alkyl;     -   R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; and     -   n is 0, 1 or 2.

This invention also relates to such a method wherein an invertebrate pest or its environment is contacted with a composition comprising a biologically effective amount of a compound of Formula I or a composition comprising a compound of Formula I and a biologically effective amount of at least one additional biologically active compound.

This invention further relates to a benzoxazinone compound of Formula 10

wherein

-   -   R⁴, R⁵, R⁶, R⁷ and R⁸ are defined as aboved in Formula I.

The compound of Formula 10 is useful as a synthetic intermediate for preparing a compound of Formula I.

DETAILS OF THE INVENTION

In the above recitations, the term “alkyl”, used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as 1-propenyl, 2-propenyl, and the different butenyl, pentynyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynes such as 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH₃OCH₂, CH₃OCH₂CH₂, CH₃CH₂OCH₂, CH₃CH₂CH₂CH₂OCH₂ and CH₃CH₂OCH₂CH₂. “Alkylthio” includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “heterocyclic ring” or heterocyclic ring system” denotes rings or ring systems in which at least one ring atom is not carbon and comprises 1 to 4 hetero atoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. The heterocyclic ring can be attached through any available carbon or nitrogen by replacement of hydrogen on said carbon or nitrogen. The term “aromatic ring system” denotes fully unsaturated carbocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic (where aromatic indicates that the Hückel rule is satisfied for the ring system). The term “heteroaromatic ring” denotes fully aromatic rings in which at least one ring atom is not carbon and comprises 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs (where aromatic indicates that the Hückel rule is satisfied). The heterocyclic ring can be attached through any available carbon or nitrogen by replacement of hydrogen on said carbon or nitrogen. The term “aromatic heterocyclic ring system” includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the Hückel rule is satisfied). The term “fused heterobicyclic ring system” includes a ring system comprised of two fused rings in which at least one ring atom is not carbon and can be aromatic or non aromatic, as defined above.

The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ and CF₃CCl₂. The terms “haloalkenyl”, “haloalkynyl”, “haloalkoxy”, and the like, are defined analogously to the term “haloalkyl”. Examples of “haloalkenyl” include (Cl)₂C═CHCH₂ and CF₃CH₂CH═CHCH₂. Examples of “haloalkynyl” include HC≡CCHCl, CCl₃C≡C and FCH₂C≡CCH₂. Examples of “haloalkoxy” include CF₃O, CCl₃CH₂O, HCF₂CH₂CH₂O and CF₃CH₂O.

The total number of carbon atoms in a substituent group is indicated by the “C_(i)-C_(j)” prefix where i and j are numbers from 1 to 8. For example, C₁-C₄ alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C₂ alkoxyalkyl designates CH₃OCH₂; C₃ alkoxyalkyl designates, for example, CH₃CH(OCH₃), CH₃OCH₂CH₂ or CH₃CH₂OCH₂; and C₄ alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH₃CH₂CH₂OCH, and CH₃CH₂OCH₂CH₂. In the above recitations, when a compound of Formula I comprises a heterocyclic ring, all substituents are attached to this ring through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.

The term “optionally substituted with one to three substituents” indicates that one to three of the available positions on the group may be substituted. When a group contains a substituent which can be hydrogen, for example R⁶, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.

Compounds of Formula I can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the compounds of Formula I may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form. Similarly, compounds of Formula 10 can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer of a compound of Formula 10 may be more useful in preparing a specific stereoisomer of Formula I. Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the compounds of Formula 10 may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

The salts of the compounds of Formula I include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.

As noted above, R⁷ is (among others) a phenyl, a benzyl, a 5- or 6-membered heteroaromatic ring, a naphthyl ring system or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R⁹. The term “optionally substituted” in connection with these R⁷ groups refers to groups which are unsubstituted or have at least one non-hydrogen substituent that does not extinguish the invertebrate pest control activity possessed by the unsubstituted analog. Note also that J-1 through J-4 below denote 5- or 6-membered heteroaromatic rings. An example of a phenyl ring optionally substituted with 1 to 3 R⁹ is the ring illustrated as J-5 in Exhibit 1, wherein r is an integer from 0 to 3. An example of a benzyl ring optionally substituted with 1 to 3 R⁹ is the ring illustrated as J-6 in Exhibit 1, wherein r is an integer from 0 to 3. An example of a naphthyl ring system optionally substituted with 1 to 3 R⁹ is illustrated as J-59 in Exhibit 1, wherein r is an integer from 0 to 3. Examples of a 5- or 6-membered heteroaromatic ring optionally substituted with 1 to 3 R⁹ include the rings J-7 through J-58 illustrated in Exhibit 1 wherein r is an integer from 0 to 3. Note that J-7 through J-26 are examples of J-1, J-27 through J-41 are examples of J-2, and J-46 through J-58 are examples of J-3 and J-4. The nitrogen atoms that require substitution to fill their valence are substituted with H or R⁹. Note that some 3 groups can only be substituted with less than 3 R⁹ groups (e.g. J-19, J-20, J-23 through J-26 and J-37 through J-40 can only be substituted with one R⁹). Examples of aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems optionally substituted with 1 to 3 R⁹ include J-60 through J-90 illustrated in Exhibit 1 wherein r is an integer from 0 to 3. Although R⁹ groups are shown in the structures J-5 through J-90, it is noted that they do not need to be present since they are optional substituents. Note that when the attachment point between (R⁹)_(r) and the 3 group is illustrated as floating, (R⁹)_(r) can be attached to any available carbon atom of the J group. Note that when the attachment point on the J group is illustrated as floating, the J group can be attached to the remainder of Formula I through any available carbon of the J group by replacement of a hydrogen atom.

Exhibit 1

Preferred methods for reasons of cost, ease of synthesis or application, and/or biological efficacy are:

Preferred 1. Methods comprising a compound of Formula I wherein

-   -   A and B are both O;     -   R⁷ is a phenyl ring or a 5- or 6-membered hetero aromatic ring         selected from the group consisting of

-   -   -   each ring optionally substituted with one to three             substituents independently selected from R⁹;

    -   Q is O, S, NH or NR⁹; and

    -   W, X, Y and Z are independently N, CH or CR⁹, provided that in         J-3 and J-4 at least one of W, X, Y or Z is N.

Preferred 2. Methods of Preferred 1 wherein

-   -   R¹, R² and R⁸ are all H;     -   R³ is C₁-C₄ alkyl optionally substituted with halogen, CN, OCH₃         or S(O)_(p)CH₃;     -   R⁴ group is attached at position 2;     -   R⁴ is CH₃, CF₃, OCF₃, OCHF₂, CN or halogen;     -   R⁵ is H, CH₃ or halogen;     -   R⁶ is CH₃, CF₃ or halogen;     -   R⁷ is phenyl or 2-pyridinyl, each optionally substituted; and     -   p is 0, 1 or 2.

Preferred 3. Methods of Preferred 2 wherein R³ is C₁-C₄ alkyl and R⁶ is CF₃.

-   -   Preferred 4. A compound of Preferred 2 wherein R³ is C₁-C₄ allyl         and R⁶ is Cl or Br.

Preferred compounds of Formula 10 are:

Preferred A. Compounds of Formula 10 wherein

-   -   R⁷ is a phenyl ring or a 5- or 6-membered heteroaromatic ring         selected from the group consisting of

-   -   -   each ring optionally substituted with one to three             substituents independently selected from R⁹;

    -   Q is O, S, NH or NR⁹; and

    -   W, X, Y and Z are independently N, CH or CR⁹, provided that in         J-3 and J-4 at least one of W, X, Y or Z is N.

Preferred B. Compounds of Preferred A wherein

-   -   R⁸ is H;     -   R⁴ group is attached at position 2;     -   R⁴ is CH₃, CF₃, OCF₃, OCHF₂, CN or halogen;     -   R⁵ is H, CH₃ or halogen;     -   R⁶ is CH₃, CF₃ or halogen; and     -   R⁷ is phenyl or 2-pyridinyl, each optionally substituted.

Preferred C. Compounds of Preferred B wherein R⁶ is CF₃.

Preferred D. Compounds of Preferred B wherein R⁶ is Cl or Br.

Of note are compounds of Formula 10 wherein R⁴ is at the 2 position and is CH₃, Cl or Br; R⁵ is at the 4 position and is F, Cl, Br, I or CF₃; R⁶ is CF₃, Cl or Br; R⁷ is 3-C₁₋₂-pyridinyl or 3-Br-2-pyridinyl; and R⁸ is H.

One or more of the following methods and variations as described in Schemes 1-22 can be used to prepare the compounds of Formula I. The definitions of A, B and R¹ through R⁹ in the compounds of Formulae 2-40 below are as defined above in the Summary of the Invention unless indicated otherwise. Compounds of Formulae Ia-d, 2a-d, 3a, 4a-d, 5a-b, 17a-c, 18a and 32a-b are various subsets of the compounds of Formula I, 2, 3, 4, 5, 17, 18 and 32. In the schemes, Het is the moiety shown below:

A typical method for preparation of a compound of Formula Ia is described in Scheme 1

The method of Scheme 1 involves coupling of an amine of Formula 2 with an acid chloride of Formula 3 in the presence of an acid scavenger to provide the compound of Formula Ia. Typical acid scavengers include amine bases such as triethylamine, N,N-diisopropylethylamine and pyridine; other scavengers include hydroxides such as sodium and potassium hydroxide and carbonates such as sodium carbonate and potassium carbonate. In certain instances it is useful to use polymer-supported acid scavengers such as polymer-bound N,N-diisopropylethylamine and polymer-bound 4-(dimethylamino)pyridine. The coupling can be run in a suitable inert solvent such as tetrahydrofuran, dioxane, diethylether or dichloromethane to afford the anilide of Formula Ia.

A thioamide of Formula Ib can be obtained in a subsequent step from the corresponding amide of Formula Ia by treatment with one of a variety of standard thio transfer reagents including phosphorus pentasulfide and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide).

As shown in Scheme 2, an alternate procedure for the preparation of compounds of Formula Ia involves coupling of an amine of Formula 2 with an acid of Formula 4 in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC), 1,1′-carbonyl-diimidazole, bis(2-oxo-3-oxazolidinyl)phosphinic chloride or benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate.

Polymer-supported reagents are again useful here, such as polymer-bound cyclohexylcarbodiimide. The coupling can be run in a suitable inert solvent such as dichloromethane or N,N-dimethylformamide. The synthetic methods of Schemes 1 and 2 are just representative examples of a wide variety of coupling methods useful for the preparation of Formula I compounds; the synthetic literature is extensive for this type of coupling reaction.

One skilled in the art will also realize that acid chlorides of Formula 3 may be prepared from acids of Formula 4 by numerous well-known methods. For example, acid chlorides of Formula 3 are readily made from carboxylic acids of Formula 4 by reacting the carboxylic acid 4 with thionyl chloride or oxalyl chloride in an inert solvent such as toluene or dichloromethane in the presence of a catalytic amount of N,N-dimethylformamide.

As shown in Scheme 3, amines of Formula 2a are typically available from the corresponding 2-nitrobenzamides of Formula 5 via catalytic hydrogenation of the nitro group.

Typical procedures involve reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon or platinum oxide and in hydroxylic solvents such as ethanol and isopropanol. Amines of Formula 2a can also be prepared by reduction with zinc in acetic acid. These procedures are well documented in the chemical literature. R¹ substituents such as C₁-C₆ alkyl can be introduced at this stage through well known methodologies including either direct alkylation or through the generally preferred method of reductive alkylation of the amine. As is further shown in Scheme 3, a commonly employed procedure is to combine the amine 2a with an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride to produce the Formula 2b compounds where R¹ is C₁-C₆ alkyl.

Scheme 4 shows that compounds of Formula Ic can be alkylated or acylated with a suitable alkylating or acylating agent such as an alkyl halide, alkyl chloroformate or acyl chloride in the presence of a base such as sodium hydride or n-butyllithium in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide to afford anilides of Formula Id wherein R¹ is other than hydrogen.

The intermediate amides of Formula 5a are readily prepared from commercially available 2-nitrobenzoic acids. Typical methods for amide formation can be used. As shown in Scheme 5, these methods include direct dehydrative coupling of acids of Formula 6 with amines of Formula 7 using for example DCC, and conversion of the acids to activated forms such as the acid chlorides or anhydrides and subsequent coupling with amines to form amides of Formula 5a.

Alkyl chloroformates, such as ethyl chloroformate or isopropyl chloroformate, are especially useful reagents for this type of reaction involving activation of the acid. The chemical literature is extensive regarding methods for amide formation. Amides of Formula 5a are readily converted to thioamides of Formula 5b by using commercially available thio transfer reagents such as phosphorus pentasulfide and Lawesson's reagent.

Intermediate anthranilic amides of Formula 2c or 2d may also be prepared from isatoic anhydrides of Formula 8 or 9, respectively, as shown in Scheme 6.

Typical procedures involve combination of equimolar amounts of the amine 7 with the isatoic anhydride in polar aprotic solvents such as pyridine and N,N-dimethylformamide at temperatures ranging from room temperature to 100° C. R¹ substituents such as alkyl and substituted alkyl may be introduced by the base-catalyzed alkylation of isatoic anhydride 8 with known alkylating reagents R¹-Lg (wherein Lg is a nucleophilic displaceable leaving group such as halide, alkyl or aryl sulfonates or alkyl sulfates) to provide the alkyl substituted intermediate 9. Isatoic anhydrides of Formula 8 may be made by methods described in Coppola, Synthesis 1980, 505-36.

As shown in Scheme 7, an alternate procedure for the preparation of specific compounds of Formula Ic involves reaction of an amine 7 with a benzoxazinone of Formula 10.

The reaction of Scheme 7 can be run neat or in a variety of suitable solvents including tetrahydrofuran, diethyl ether, pyridine, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the reflux temperature of the solvent. The general reaction of benzoxazinones with amines to produce anthranilamides is well documented in the chemical literature. For a review of benzoxazinone chemistry see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and references cited therein. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

Benzoxazinones of Formula 10 can be prepared by a variety of procedures. Two procedures that are especially useful are detailed in Schemes 8-9. In Scheme 8, a benzoxazinone of Formula 10 is prepared directly via coupling of a pyrazolecarboxylic acid of Formula 4a with an anthranilic acid of Formula 11.

This involves sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 4a, followed by the addition of an anthranilic acid of Formula 11, followed by a second addition of tertiary amine and methanesulfonyl chloride. This procedure generally affords good yields of the benzoxazinone and is illustrated with greater detail in Examples 6 and 8.

Scheme 9 depicts an alternate preparation for benzoxazinones of Formula 10 involving coupling of a pyrazole acid chloride of Formula 3a with an isatoic anhydride of Formula 8 to provide the Formula 10 benzoxszinone directly.

Solvents such as pyridine or pyridine/acetonitrile are suitable for this reaction. The acid chlorides of Formula 3a are available from the corresponding acids of Formula 4a by a variety of synthetic methods such as chlorination with thionyl chloride or oxalyl chloride.

Isatoic anhydrides of Formula 8 can be prepared from isatins of Formula 13 as outlined in Scheme 10.

Isatins of Formula 13 are obtained from aniline derivatives of Formula 12 using methods known in the literature. Oxidation of isatin 13 with hydrogen peroxide generally affords good yields of the corresponding isatoic anhydride 8 (Angew. Chem. Int. Ed. Engl. 1980, 19, 222-223). Isatoic anhydrides are also available from the anthranilic acids 11 via many known procedures involving reaction of 11 with phosgene or a phosgene equivalent.

The syntheses of representative acids of Formula 4 are depicted in Schemes 11-16. Syntheses of pyrazoles of Formula 4a are shown in Scheme 11.

The synthesis of compounds of Formula 4a in Scheme 11 involves as the key step introduction of the R⁷ substituent via alkylation or arylation of the pyrazole of Formula 14 with compounds of Formula 15 (wherein Lg is a leaving group as defined above). Oxidation of the methyl group affords the pyrazole carboxylic acid. Some of the more preferred R⁶ groups include haloalkyl.

Synthesis of pyrazoles of Formula 4a is also shown in Scheme 12.

These acids may be prepared via metallation and carboxylation of compounds of Formula 18 as the key step. The R⁷ group is introduced in a manner similar to that of Scheme 11, i.e. via alkylation or arylation with a compound of Formula 15. Representative R⁶ groups include e.g. cyano, haloalkyl and halogen.

This procedure is particularly useful for preparing 1-(2-pyridinyl)pyrazolecarboxylic acids of Formula 4b as shown in Scheme 13.

Reaction of a pyrazole of Formula 17 with a 2,3-dihalopyridine of Formula 15a affords good yields of the 1-pyridylpyrazole of Formula 18a with good specificity for the desired regiochemistry. Metallation of 18a with lithium diisopropylamide (LDA) followed by quenching of the lithium salt with carbon dioxide affords the 1-(2-pyridinyl)pyrazole-carboxylic acid of Formula 4b. Additional details for these procedures are provided in Examples 1, 3, 6, 8 and 10.

The synthesis of pyrazoles of Formula 4c is described in Scheme 14.

Scheme 14 involves reaction of an optionally substituted phenyl hydrazine of Formula 19 with a ketopyruvate of Formula 20 to yield pyrazole esters of Formula 21. Hydrolysis of the esters affords the pyrazole acids of Formula 4c. This procedure is particularly useful for the preparation of compounds in which R⁷ is optionally substituted phenyl and R⁶ is haloalkyl.

An alternate synthesis of pyrazole acids of Formula 4c is described in Scheme 15.

The method of Scheme 15 involves 3+2 cycloaddition of an appropriately substituted iminohalide 22 with either substituted propiolates of Formula 23 or acrylates of Formula 25. Cycloaddition with an acrylate requires additional oxidation of the intermediate pyrazoline to the pyrazole. Hydrolysis of the esters affords the pyrazole acids of Formula 4c. Preferred iminohalides for this reaction include the trifluoromethyl iminochloride of Formula 26 and the iminodibromide of Formula 27. Compounds such as 26 are known (J. Heterocycl. Chem. 1985, 22(2), 565-8). Compounds such as 27 are available by known methods (Tetrahedron Letters 1999, 40, 2605). These procedures are particularly useful for the preparation of compounds where R⁷ is optionally substituted phenyl and R⁶ is haloalkyl or bromo.

The starting pyrazoles of Formula 17 are known compounds or can be prepared according to known methods. The pyrazole of Formula 17a (the compound of Formula 17 wherein R⁶ is CF₃ and R⁸ is H) can be prepared by literature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). The pyrazoles of Formula 17c (compounds of Formula 17 wherein R⁶ is Cl or Br and R⁸ is H) can also be prepared by literature procedures (Chem. Ber. 1966, 99(10), 3350-7). A useful alternative method for the preparation of compound 17c is depicted in Scheme 16.

In the method of Scheme 16, metallation of the sulfamoyl pyrazole of Formula 28 with n-butyllithium followed by direct halogenation of the anion with either hexachloroethane (for R⁶ being Cl) or 1,2-dibromotetrachloroethane (for R⁶ being Br) affords the halogenated derivatives of Formula 29. Removal of the sulfamoyl group with trifluoroacetic acid (TFA) at room temperature proceeds cleanly and in good yield to afford the pyrazoles of Formula 17c. One skilled in the art will recognize that Formula 17c is a tautomer of Formula 17b. Further experimental details for these procedures are described in Examples 8 and 10.

Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is H, C₁-C₆ alkyl or C₁-C₆ haloalkyl can be prepared by the method outlined in Scheme 17.

Reaction of a compound of Formula 30 wherein R¹³ is C₁-C₄ alkyl with a suitable base in a suitable organic solvent affords the cyclized product of Formula 31 after neutralization with an acid such as acetic acid. The suitable base can be, for example but not limitation, sodium hydride, potassium t-butoxide, dimsyl sodium (CH₃S(O)CH₂ ⁻Na⁺), alkali metal (such as lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphonine. The suitable organic solvent can be, for example but not limitation, acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylsulfoxide, or N,N-dimethylformamide. The cyclization reaction is usually conducted in a temperature range from about 0 to 120° C. The effects of solvent, base, temperature and addition time are all interdependent, and choice of reaction conditions is important to minimize the formation of byproducts. A preferred base is tetrabutylammonium fluoride.

Dehydration of the compound of Formula 31 to give the compound of Formula 32, followed by converting the carboxylic ester function to carboxylic acid, affords the compound of Formula 4d. The dehydration is effected by treatment with a catalytic amount of a suitable acid. This catalytic acid can be, for example but not limitation, sulfuric acid. The reaction is generally conducted using an organic solvent. As one skilled in the art will realize, dehydration reactions may be conducted in a wide variety of solvents in a temperature range generally between about 0 and 200° C., more preferably between about 0 and 100° C. For the dehydration in the method of Scheme 17, a solvent comprising acetic acid and temperatures of about 65° C. are preferred. Carboxylic ester compounds can be converted to carboxylic acid compounds by numerous methods including nucleophilic cleavage under anhydrous conditions or hydrolytic methods involving the use of either acids or bases (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). For the method of Scheme 17, base-catalyzed hydrolytic methods are preferred. Suitable bases include alkali metal (such as lithium, sodium or potassium) hydroxides. For example, the ester can be dissolved in a mixture of water and an alcohol such as ethanol. Upon treatment with sodium hydroxide or potassium hydroxide, the ester is saponified to provide the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of Formula 4d. The carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

Compounds of Formula 30 can be prepared by the method outlined in Scheme 18.

wherein R⁶ is H, C₁-C₆ alkyl or C₁-C₆ haloalkyl and R¹³ is C₁-C₄ alkyl.

Treatment of a hydrazine compound of Formula 33 with a ketone of Formula 34 in a solvent such as water, methanol or acetic acid gives the hydrazone of Formula 35. One skilled in the art will recognize that this reaction may require catalysis by an optional acid and may also require elevated temperatures depending on the molecular substitution pattern of the hydrazone of Formula 35. Reaction of the hydrazone of Formula 35 with the compound of Formula 36 in a suitable organic solvent such as, for example but not limitation, dichloromethane or tetrahydrofuran in the presence of an acid scavenger such as triethylamine provides the compound of Formula 30. The reaction is usually conducted at a temperature between about 0 and 100° C. Further experimental details for the method of Scheme 18 are illustrated in Example 17. Hydrazine compounds of Formula 33 can be prepared by standard methods, such as by contacting the corresponding halo compound of Formula 15a with hydrazine.

Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is halogen can be prepared by the method outlined in Scheme 19.

wherein R¹³ is C₁-C₄ alkyl.

Oxidization of the compound of Formula 37 optionally in the presence of acid to give the compound of Formula 32 followed by conversion of the carboxylic ester function to the carboxylic acid provides the compound of Formula 4d. The oxidizing agent can be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. To obtain complete conversion, at least one equivalent of oxidizing agent versus the compound of Formula 37 should be used, preferably between about one to two equivalents. This oxidation is typically carried out in the presence of a solvent. The solvent can be an ether, such as tetrahydrofuran, p-dioxane and the like, an organic ester, such as ethyl acetate, dimethyl carbonate and the like, or a polar aprotic organic such as N,N-dimethylformamide, acetonitrile and the like. Acids suitable for use in the oxidation step include inorganic acids, such as sulfuric acid, phosphoric acid and the like, and organic acids, such as acetic acid, benzoic acid and the like. The acid, when used, should be used in greater than 0.1 equivalents versus the compound of Formula 37. To obtain complete conversion, one to five equivalents of acid can be used. The preferred oxidant is potassium persulfate and the oxidation is preferably carried out in the presence of sulfuric acid. The reaction can be carried out by mixing the compound of Formula 37 in the desired solvent and, if used, the acid. The oxidant can then be added at a convenient rate. The reaction temperature is typically varied from as low as about 0° C. up to the boiling point of the solvent in order to obtain a reasonable reaction time to complete the reaction, preferably less than 8 hours. The desired product, a compound of Formula 32 can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation. Methods suitable for converting the ester of Formula 32 to the carboxylic acid of Formula 4d are already described for Scheme 17. Further experimental details for the method of Scheme 19 are illustrated in Examples 12 and 13.

Compounds of Formula 37 can be prepared from corresponding compounds of Formula 38 as shown in Scheme 20.

wherein R¹³ is C₁-C₄ alkyl and R⁶ is halogen.

Treatment of a compound of Formula 38 with a halogenating reagent, usually in the presence of a solvent, affords the corresponding halo compound of Formula 37. Halogenating reagents that can be used include phosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides, thionyl chloride, dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred are phosphorus oxyhalides and phosphorus pentahalides. To obtain complete conversion, at least 0.33 equivalents of phosphorus oxyhalide versus the compound of Formula 38 (i.e. the mole reatio of phosphorus oxyhalide to Formula 18 is at least 0.33) should be used, preferably between about 0.33 and 1.2 equivalents. To obtain complete conversion, at least 0.20 equivalents of phosphorus pentahalide versus the compound of Formula 38 should be used, preferably between about 0.20 and 1.0 equivalents. Compounds of Formula 38 wherein R¹³ is C₁-C₄ alkyl are preferred for this reaction. Typical solvents for this halogenation include halogenated alkanes, such as dichloromethane, chloroform, chlorobutane and the like, aromatic solvents, such as benzene, xylene, chlorobenzene and the like, ethers, such as tetrahydrofuran, p-dioxane, diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like. Optionally, an organic base, such as triethylamine, pyridine, N,N-dimethylaniline or the like, can be added. Addition of a catalyst, such as N,N-dimethylformamide, is also an option. Preferred is the process in which the solvent is acetonitrile and a base is absent. Typically, neither a base nor a catalyst is required when acetonitrile solvent is used. The preferred process is conducted by mixing the compound of Formula 38 in acetonitrile. The halogenating reagent is then added over a convenient time, and the mixture is then held at the desired temperature until the reaction is complete. The reaction temperature is typically between 20° C. and the boiling point of acetonitrile, and the reaction time is typically less than 2 hours. The reaction mass is then neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide and the like, or an organic base, such as sodium acetate. The desired product, a compound of Formula 37, can be isolated by methods known to those skilled in the art, including crystallization, extraction and distillation.

Alternatively, compounds of Formula 37 wherein R⁶ is halogen can be prepared by treating the corresponding compounds of Formula 37 wherein R⁶ is a different halogen (e.g., Cl for making Formula 37 wherein R³ is Br) or a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate with the appropriate hydrogen halide. By this method the R⁶ halogen or sulfonate substituent on the Formula 37 starting compound is replaced with, for example, Br or Cl from hydrogen bromide or hydrogen chloride, respectively. The reaction is conducted in a suitable solvent such as dibromomethane, dichloromethane or acetonitrile. The reaction can be conducted at or near atmospheric pressure or above atmospheric pressure in a pressure vessel. When R⁶ in the starting compound of Formula 37 is a halogen such as Cl, the reaction is preferably conducted in such a way that the hydrogen halide generated from the reaction is removed by sparging or other suitable means. The reaction can be conducted between about 0 and 100° C., most conveniently near ambient temperature (e.g., about 10 to 40° C.), and more preferably between about 20 and 30° C. Addition of a Lewis acid catalyst (such as aluminum tribromide for preparing Formula 37 wherein R⁶ is Br) can facilitate the reaction. The product of Formula 37 is isolated by the usual methods known to those skilled in the art, including extraction, distillation and crystallization. Further details for this process are illustrated in Example 14.

Starting compounds of Formula 37 wherein R⁶ is Cl or Br can be prepared from corresponding compounds of Formula 38 as already described. Starting compounds of Formula 37 wherein R⁶ is a sulfonate group can likewise be prepared from corresponding compounds of Formula 38 by standard methods such as treatment with a sulfonyl chloride (e.g., p-toluenesulfonyl chloride) and base such as a tertiary amine (e.g., triethylamine) in a suitable solvent such as dichloromethane; further details for this process are illustrated in Example 15.

Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is C₁-C₄ alkoxy or C₁-C₄ haloalkoxy can also be prepared by the method outlined in Scheme 21.

wherein R¹³ is C₁-C₄ alkyl, and X is a leaving group.

In this method, instead of being halogenated as shown in Scheme 20, the compound of Formula 38 is oxidized to the compound of Formula 32a. The reaction conditions for this oxidation are as already described for the conversion of the compound of Formula 37 to the compound of Formula 32 in Scheme 19.

The compound of Formula 32a is then alkylated to form the compound of Formula 32b by contact with an alkylating agent CF₃CH₂X (39) in the presence of a base. In the alkylating agent 39, X is a nucleophilic reaction leaving group such as halogen (e.g., Br, I), OS(O)₂CH₃ (methanesulfonate), OS(O)₂CF₃, OS(O)₂Ph-p-CH₃ (p-toluenesulfonate), and the like; methanesulfonate works well. The reaction is conducted in the presence of at least one equivalent of a base. Suitable bases include inorganic bases, such as alkali metal (such as lithium, sodium or potassium) carbonates and hydroxides, and organic bases, such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conducted in a solvent, which can comprise alcohols, such as methanol and ethanol, halogenated alkanes, such as dichloromethane, aromatic solvents, such as benzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, and polar aprotic solvents, such as acetonitrile, such as such as acetonitrile, N,N-dimethylformamide, and the like. Alcohols and polar aprotic solvents are preferred for use with inorganic bases. Potassium carbonate as base and acetonitrile as solvent are preferred. The reaction is generally conducted between about 0 and 150° C., with most typically between ambient temperature and 100° C. The product of Formula 32b can be isolated by conventional techniques such as extraction. The ester of Formula 32b can then be converted to the carboxylic acid of Formula 4d by the methods already described for the conversion of Formula 32 to Formula 4d in Scheme 17. Further experimental details for the method of Scheme 21 are illustrated in Example 16.

Compounds of Formula 38 can be prepared from compounds of Formula 33 as outlined in Scheme 22.

wherein R¹³ is C₁-C₄ alkyl.

In this method, a hydrazine compound of Formula 33 is contacted with a compound of Formula 40 (a fumarate ester or maleate ester or a mixture thereof may be used) in the presence of a base and a solvent. The base is typically a metal alkoxide salt, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, and the like. Greater than 0.5 equivalents of base versus the compound of Formula 33 should be used, preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalents of the compound of Formula 40 should be used, preferably between 1.0 to 1.3 equivalents. Polar protic and polar aprotic organic solvents can be used, such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferred solvents are alcohols such as methanol and ethanol. It is especially preferred that the alcohol be the same as that making up the fumarate or maleate ester and the alkoxide base. The reaction is typically conducted by mixing the compound of Formula 33 and the base in the solvent. The mixture can be heated or cooled to a desired temperature and the compound of Formula 40 added over a period of time. Typically reaction temperatures are between 0° C. and the boiling point of the solvent used. The reaction may be conducted under greater than atmospheric pressure in order to increase the boiling point of the solvent. Temperatures between about 30 and 90° C. are generally preferred. The addition time can be as quick as heat transfer allows. Typical addition times are between 1 minute and 2 hours. Optimum reaction temperature and addition time vary depending upon the identities of the compounds of Formula 33 and Formula 40. After addition, the reaction mixture can be held for a time at the reaction temperature. Depending upon the reaction temperature, the required hold time may be from 0 to 2 hours. Typical hold times are 10 to 60 minutes. The reaction mass then can be acidified by adding an organic acid, such as acetic acid and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid and the like. Depending on the reaction conditions and the means of isolation, the —CO₂R¹³ function on the compound of Formula 38 may be hydrolyzed to —CO₂H; for example, the presence of water in the reaction mixture can promote such hydrolysis. If the carboxylic acid (—CO₂H) is formed, it can be converted back to —CO₂R¹³ wherein R¹³ is C₁-C₄ alkyl using esterification methods well-known in the art. The desired product, a compound of Formula 38, can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.

It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.

It is believed that one skilled in the art using the preceding description can prepare compounds of Formula I of the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. ¹H NMR spectra are reported in ppm downfield from tetramethylsilane; s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, dd means doublet of doublets, dt means doublet of triplets, br s means broad singlet.

Example 1 Preparation of 2-[1-Ethyl-3-trifluoromethylpyrazyl-5-yl carbamoyl]-3-methyl-N-(1-methylethyl)benzamide Step A: Preparation of 3-Methyl-N-(1-methylethyl)-2-nitrobenzamide

A solution of 3-methyl-2-nitrobenzoic acid (2.00 g, 11.0 mmol) and triethylamine (1.22 g, 12.1 mmol) in 25 mL of methylene chloride was cooled to 10° C. Ethyl chloroformate was carefully added and a solid precipitate formed. After stifling for 30 minutes isopropylamine (0.94 g, 16.0 mmol) was added and a homogeneous solution resulted. The reaction was stirred for an additional hour, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to afford 1.96 g of the desired intermediate as a white solid melting at 126-128° C.

¹H NMR (CDCl₃) δ 1.24 (d, 6H), 2.38 (s, 3H), 4.22 (m, 1H), 5.80 (br s, 1H), 7.4 (m, 3H).

Step B: Preparation of 2-Amino-3-methyl-N-(1-methylethyl)benzamide

The 2-nitrobenzamide of Step A (1.70 g, 7.6 mmol) was hydrogenated over 5% Pd/C in 40 mL of ethanol at 50 psi. When the uptake of hydrogen ceased the reaction was filtered through Celite® diatomaceous filter aid and the Celite® was washed with ether. The filtrate was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151° C.

¹H NMR (CDCl₃) δ 1.24 (dd, 6H), 2.16 (s, 3H), 4.25 (m, 1H), 5.54 (br s, 2H), 5.85 (br s, 1H), 6.59 (t, 1H), 7.13 (d, 1H), 7.17 (d, 1H).

Step C: Preparation of 1-Ethyl-3-trifluoromethylpyrazol-5-yl carboxylic acid

To a mixture of 3-trifluoromethylpyrazole (5 g, 37 mmol) and powdered potassium carbonate (10 g, 72 mmol) stirring in 30 mL of N,N-dimethylformamide, iodoethane (8 g, 51 mmol) was added dropwise. After a mild exotherm, the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between 100 mL of diethyl ether and 100 mL of water. The ether layer was separated, washed with water (3×) and brine, and dried over magnesium sulfate. Evaporation of solvent in vacuo gave 4 g of oil.

To 3.8 g of this oil stirring in 40 mL of tetrahydrofuran under nitrogen in a dry ice/acetone bath, 17 mL of a 2.5 M solution of n-butyllithium in tetrahydrofuran (43 mmol) was added dropwise and the solution stirred for 20 minutes at −78° C. An excess of gaseous carbon dioxide was bubbled into the stirred solution at a moderate rate for 10 minutes. After addition of carbon dioxide, the reaction was allowed to slowly reach room temperature and stirred overnight. The reaction mixture was partitioned between diethyl ether (100 mL) and 0.5 N aqueous sodium hydroxide (100 mL). The basic layer was separated and acidified with concentrated hydrochloric acid to a pH of 2-3. The aqueous mixture was extracted with ethyl acetate (100 mL) and the organic extract washed with water and brine and dried over magnesium sulfate. The oily residue, which remained after evaporating the solvent in vacuo, was triturated to a solid from a small amount of 1-chlorobutane. After filtering and drying, a slightly impure sample of 1-ethyl-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (1.4 g) was obtained as a broad-melting solid.

¹H NMR (CDCl₃) δ 1.51 (t, 3H), 4.68 (q, 2H), 7.23 (s, 1H), 9.85 (br s, 1H).

Step D: Preparation of 2-[1-Ethyl-3-trifluoromethylpyrazol-5-yl carbamoyl]-3-methyl-N-(1-methylethyl)benzamide

To a solution of 1-ethyl-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (i.e. the product of Step C) (0.5 g, 2.4 mmol) stirring in 20 mL of methylene chloride, oxalyl chloride (1.2 mL, 14 mmol) was added. Upon addition of 2 drops of N,N-dimethylformamide, foaming and bubbling occurred. The reaction mixture was heated at reflux for 1 hr as a yellow solution. After cooling, the solvent was removed in vacuo and the resulting residue dissolved in 20 mL of tetrahydrofuran. To the stirred solution, 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. the product of Step B) (0.7 g, 3.6 mmol) was added followed by the dropwise addition of N,N-diisopropylethylamine (3 mL, 17 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between ethyl acetate (100 mL) and 1N aqueous hydrochloric acid (75 mL). The separated organic layer was washed with water and brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid residue, which on purification by flash column chromatography on silica gel (2:1 hexanes/ethyl acetate) afforded 0.5 g of the title compound, a compound of the present invention, melting at 223-226° C.

¹H NMR (DMSO-d₆) δ 1.06 (d, 6H), 1.36 (t, 3H), 2.45 (s, 3H), 3.97 (m, 1H), 4.58 (q, 2H), 7.43-7.25 (m, 3H), 7.45 (s, 1H), 8.05 (d, 1H), 10.15 (s, 1H).

Example 2 Preparation of N-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide Step A: Preparation of 2-Methyl-1-phenyl-4-(trifluoromethyl)-1H-pyrazole

A solution of 1,1,1-trifluoropentane-2,4-dione (20.0 g, 0.130 mole) in glacial acetic acid (60 mL) was cooled to 7° C. using an ice/water bath. Phenylhydrazine (14.1 g, 0.130 mole) was added dropwise over a period of 60 minutes. The reaction mass temperature increased to 15° C. during the addition. The resulting orange solution was held under ambient conditions for 60 minutes. The bulk of the acetic acid was removed by stripping on a rotary evaporator at a bath temperature of 65° C. The residue was dissolved in methylene chloride (150 mL). The solution was washed with aqueous sodium bicarbonate (3 g in 50 mL of water). The purple-red organic layer was separated, treated with activated charcoal (2 g) and MgSO₄, then filtered. Volatiles were removed on a rotary evaporator. The crude product consisted of 28.0 g of a rose-colored oil, which contained ˜89% the desired product and 11% 1-phenyl-5-(trifluoromethyl)-3-methylpyrazole.

¹H NMR (DMSO-d₆) δ 2.35 (s, 3H), 6.76 (s, 1H), 7.6-7.5 (m, 5H).

Step B: Preparation of 1-Phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

A sample of crude 2-methyl-1-phenyl-4-(trifluoromethyl)-1H-pyrazole (i.e. the product of Step A) (˜89%, 50.0 g, 0.221 mole) was mixed with water (400 mL) and cetyltrimethylammonium chloride (4.00 g, 0.011 mole). The mixture was heated to 95° C. Potassium permanganate was added in 10 equal portions, spaced at ˜8 minute intervals. The reaction mass was maintained at 95-100° C. during this period. After the last portion was added, the mixture was held for ˜15 minutes at 95-100° C., whereupon the purple, permanganate color had been discharged. The reaction mass was filtered while hot (˜75° C.) through a 1-cm bed of Celite® diatomaceous filter aid in a 150-mL coarse glass frit funnel. The filter cake was washed with warm (˜50° C.) water (3×100 mL). The combined filtrate and washings were extracted with ether (2×100 mL) to remove a small amount of yellow, water-insoluble material. The aqueous layer was purged with nitrogen to remove residual ether. The clear, colorless alkaline solution was acidified by adding concentrated hydrochloric acid dropwise until the pH reached ˜1.3 (28 g, 0.28 mole). Gas evolution was vigorous during the first two-thirds of the addition. The product was collected via filtration, washed with water (3×40 mL), then dried overnight at 55° C. in vacuo. The product consisted of 11.7 g of a white, crystalline powder, which was essentially pure based upon ¹H NMR.

¹H NMR (CDCl₃) δ 7.33 (s, 1H), 7.4-7.5 (m, 5H).

Step C: Preparation of 1-Phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride

A sample of crude 1-phenyl-3-(trifluoromethyl)pyrazole-5-carboxylic acid (i.e. the product of Step B) (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45 mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol), followed by N,N-dimethylformamide (0.010 mL, 0.13 mmol). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for ˜20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by stripping the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The product consisted of 4.43 g of a light-yellow oil. The only impurity observed by ¹H NMR was N,N-dimethylformamide.

¹H NMR (CDCl₃) δ 7.40 (m, 1H), 7.42 (s, 1H), 7.50-7.53 (m, 4H).

Step D: Preparation of N-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

A sample of 3-methylisatoic anhydride (0.30 g, 1.7 mmol) partially dissolved in pyridine (4.0 mL) was treated with 1-phenyl-3-(trifluoromethylpyrazole)-5-carboxyl chloride (i.e. the product of Step C) (0.55 g, 1.9 mmol). The mixture was heated to ˜95° C. for a period of 2 hours. The resulting orange solution was cooled to 29° C., then was treated with isopropylamine (1.00 g, 16.9 mmol). The reaction mass exothermically warmed to 39° C. It was further heated to 55° C. for a period of 30 minutes, whereupon much precipitate formed. The reaction mass was dissolved in dichloromethane (150 mL). The solution was washed with aqueous acid (5 mL of conc. HCl in 45 mL of water), then with aqueous base (2 g sodium carbonate in 50 mL of water). The organic layer was dried over MgSO₄, filtered, then concentrated on a rotary evaporator. Upon reduction to ˜4 mL, product crystals had formed. The slurry was diluted with ˜10 mL of ether, whereupon more product precipitated. The product was isolated by filtration, washed with ether (2×10 mL), then washed with water (2×50 mL). The wet cake was dried for 30 minutes at 70° C. in vacuo. The product, a compound of the present invention, consisted of 0.52 g of an off-white powder melting at 260-262° C.

¹H NMR (DMSO-d₆) δ 1.07 (d, 6H), 2.21 (s, 3H), 4.02 (octet, 1H), 7.2-7.4 (m, 3H), 7.45-7.6 (m, 6H), 8.10 (d, 1H), 10.31 (s, 1H).

Example 3

Preparation N-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxamide

Step A: Preparation of 3-Trifluoromethyl-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

A mixture of 2-chloro-3-trifluoromethylpyridine (3.62 g., 21 mmol), 3-trifluoro-methylpyrazole (2.7 g., 20 mmol), and potassium carbonate (6.0 g, 43 mmol) were heated at 100° C. for 18 h. The cooled reaction mixture was added to ice/water (100 mL). The mixture was extracted twice with ether (100 mL) and the combined ether extracts were washed twice with water (100 mL). The organic layer was dried with magnesium sulfate and concentrated to an oil. Chromatography on silica gel with hexanes:ethyl acetate (8:1 to 4:1) as eluent gave the title compound (3.5 g) as an oil.

¹H NMR (CDCl₃) δ 6.75 (m, 1H), 7.5 (m, 1H), 8.2 (m, 2H), 8.7 (m, 1H).

Step B: Preparation of 3-(Trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxylic acid

A mixture of the title compound of Example 3, Step A (3.4 g, 13 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to −70° C. Lithium diisopropylamide (2N in heptane/tetrahydrofuran, (Aldrich) 9.5 mL, 19 mmol) was added and the resulting dark mixture was stirred for 10 minutes. Dry carbon dioxide was bubbled through the mixture for 15 minutes. The mixture was allowed to warm to 23° C. and treated with water (50 mL) and 1N sodium hydroxide (10 mL). The aqueous mixture was extracted with ether (100 mL) and then ethyl acetate (100 mL). The aqueous layer was acidified with 6N hydrochloric acid to pH 1-2 and extracted twice with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated to give the title compound (1.5 g).

¹H NMR(CDCl₃) δ 7.6 (m, 1H), 7.95 (m, 1H), 8.56 (m, 1H), 8.9 (m, 1H), 14.2 (br, 1H)

Step C: Preparation of N-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxamide

A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1 mmol) in acetonitrile (13 mL) was treated with triethylamine (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g), a compound of the present invention, was isolated as a white solid. m.p. 227-230° C.

¹H NMR (CDCl₃) δ 1.2 (m, 6H), 4.15 (m, 1H), 5.9 (br d, 1H), 7.1 (m, 1H), 7.2 (m, 2H), 7.4 (s, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.74 (m, 1H), 10.4 (br, 1H).

Example 4 Preparation of 1-(3-Chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]carbonyl-phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide Step A: Preparation of 3-Chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atmospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141° C., 7 mm) afforded the desired intermediate as a clear yellow oil (113.4 g).

¹H NMR (CDCl₃) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).

Step B: Preparation of 1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

To a solution of 3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (i.e. the product of Step A) (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL) at −75° C. was added via cannula a −30° C. solution of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deep red solution was stirred for 15 minutes, after which time carbon dioxide was bubbled through at −63° C. until the solution became pale yellow and the exothermicity ceased. The reaction was stirred for an additional 20 minutes and then quenched with water (20 mL). The solvent was removed under reduced pressure, and the reaction mixture partitioned between ether and 0.5N aqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3×), filtered through Celite® diatomaceous filter aid to remove residual solids, and then acidified to a pH of approximately 4, at which point an orange oil formed. The aqueous mixture was stirred vigorously and additional acid was added to lower the pH to 2.5-3. The orange oil congealed into a granular solid, which was filtered, washed successively with water and 1N hydrochloric acid, and dried under vacuum at 50° C. to afford the title product as an off-white solid (130 g). (Product from another run following similar procedures melted at 175-176° C.)

¹H NMR (DMSO-d₆) δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).

Step C: Preparation of 8-Methyl-2H-3,1-benzoxazine-2,4(1H)-dione

To a solution of 2-amino-3-methylbenzoic acid (6 g) in dry 1,4-dioxane (50 mL) was added dropwise a solution of trichloromethyl chloroformate (8 mL) in dry 1,4-dioxane (25 mL), with ice-water cooling to keep the reaction temperature below 25° C. A white precipitate began to form during the addition. The reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and washed with 1,4-dioxane (2×20 mL) and hexane (2×15 mL) and air-dried to yield 6.51 g of off-white solid.

¹H NMR (DMSO-d₆) δ 2.33 (s, 3H), 7.18 (t, 1H), 7.59 (d, 1H), 7.78 (d, 1H), 11.0 (br s, 1H).

Step D: Preparation of 2-[1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

To a suspension of the carboxylic acid product prepared as in Step B (146 g, 500 mmol) in dichloromethane (approximately 2 L) was added N,N-dimethylformamide (20 drops) and oxalyl chloride (67 mL, 750 mmol) in approximately 5-mL portions over approximately 2 h. Vigorous gas evolution occurred during the addition. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to provide the crude acid chloride as an opaque orange mixture. This material was taken up in dichloromethane, filtered to remove some solids and then reconcentrated and used without further purification. The crude acid chloride was dissolved in acetonitrile (250 mL) and added to a suspension of the product from Step C in acetonitrile (400 mL). Pyridine (250 mL) was added, the mixture was stirred for 15 min at room temperature, then warmed to reflux for 3 h. The resulting mixture was cooled to room temperature and stirred overnight to provide a solid mass. Additional acetonitrile was added and the mixture was mixed to form a thick slurry. The solids were collected and washed with cold acetonitrile. The solids were air-dried and the dried in vacuo at 90° C. for 5 h to yield 144.8 g of fluffy white solid.

¹H NMR (CDCl₃) δ 1.84 (s, 3H), 7.4 (t, 1H), 7.6 (m, 3H), 8.0 (dd, 1H), 8.1 (s, 1H), 8.6 (d, 1H).

Step E: Preparation of 1-(3-Chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)-amino]carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a suspension of the benzoxazinone product of Step D (124 g, 300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine (76 mL, 900 mmol) at room temperature. The temperature of the reaction mixture rose and the suspension thinned during the addition. The reaction mixture was then warmed to reflux for 1.5 h. A new suspension formed. The reaction mixture was cooled to room temperature and diethyl ether (1.3 L) was added and the mixture stirred at room temperature overnight. The solids were collected and washed with ether. The solids were air-dried and then dried in vacuo at 90° C. for 5 h to yield 122 g of the title compound, a compound of the present invention, as a fluffy white solid, melting at 194-196° C.

¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 10.4 (s, 1H).

Example 5 Alternate preparation of 1-(3-chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of the carboxylic acid product prepared as in Example 4, Step B (28 g, 96 mmol) in dichloromethane (240 mL) was added N,N-dimethylformamide (12 drops) and oxalyl chloride (15.8 g, 124 mmol). The reaction mixture was stirred at room temperature until gas evolution ceased (approximately 1.5 h). The reaction mixture was concentrated in vacuo to provide the crude acid chloride as an oil that was used without further purification. The crude acid chloride was dissolved in acetonitrile (95 mL) and added to a solution of the benzoxazin-2,4-dione prepared as in Example 4, Step C in acetonitrile (95 mL). The resulting mixture was stirred at room temperature (approximately 30 min). Pyridine (95 mL) was added and the mixture heated to about 90° C. (approximately 1 h). The reaction mixture was cooled to about 35° C. and isopropylamine (25 mL) was added. The reaction mixture exothermically warmed during the addition and then was maintained at about 50° C. (approximately 1 h). The reaction mixture was then poured into ice water and stirred. The resulting precipitate was collected by filtration, washed with water and dried in vacuo overnight to provide 37.5 g of the title compound, a compound of the present invention, as a tan solid.

¹H NMR. (CDCl₃) δ 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d, 1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H), 8.5 (d, 1H), 10.4 (s, 1H).

Example 6 Preparation of N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide Step A: Preparation of 2-Amino-3-methyl-5-chlorobenzoic acid

To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100° C. for 30 minutes. The heat was removed, the reaction was cooled to room temperature and let stand overnight. The reaction mixture was then slowly poured into ice-water (250 mL) to precipitate a white solid. The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g).

¹H NMR (DMSO-d₆) δ 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).

Step B: Preparation of 3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethylpyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atomospheric pressure. Distillation of the product at reduced pressure (b.p. 139-141° C., 7 mm) afforded the title compound as a clear yellow oil (113.4 g).

¹H NMR (CDCl₃) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).

Step C: Preparation of 1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

To a solution of the pyrazole product from Step B (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL) at −75° C. was added via cannula a −30° C. solution of lithium diisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deep red solution was stirred for 15 minutes, after which time carbon dioxide was bubbled through at −63° C. until the solution became pale yellow and the exothermicity ceased. The reaction was stirred for an additional 20 minutes and then quenched with water (20 mL). The solvent was removed under reduced pressure, and the reaction mixture was partitioned between ether and 0.5 N aqueous sodium hydroxide solution. The aqueous extracts were washed with ether (3×), filtered through Celite® diatomaceous filter aid to remove residual solids, and then acidified to a pH of approximately 4, at which point an orange oil formed. The aqueous mixture was stirred vigorously and additional acid was added to lower the pH to 2.5-3. The orange oil congealed into a granular solid, which was filtered, washed successively with water and 1N hydrochloric acid, and dried under vacuum at 50° C. to afford the title product as an off-white solid (130 g). (Product from another run following similar procedure melted at 175-176° C.)

¹H NMR (DMSO-d₆) δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d, 1H).

Step D: Preparation of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in acetonitrile (75 mL) was added dropwise a mixture of the carboxylic acid product from Step C (7.5 g, 27.0 mmol) and triethylamine (3.75 mL, 27.0 mmol) in acetonitrile (75 mL) at 0-5° C. The reaction temperature was then maintained at 0° C. throughout successive addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-chlorobenzoic acid from Step A (5.1 g, 27.0 mmol) was added and stirring was continued for an additional 5 minutes. A solution of triethylamine (7.5 mL, 54.0 mmol) in acetonitrile (15 mL) was then added dropwise, and the reaction mixture was stirred 45 minutes, followed by the addition of methanesulfonyl chloride (2.2 mL, 28.3 mmol). The reaction mixture was then warmed to room temperature and stirred overnight. Approximately 75 mL of water was then added to precipitate 5.8 g of a yellow solid. An additional 1 g of product was isolated by extraction from the filtrate to provide a total of 6.8 g of the title compound as a yellow solid.

¹H NMR (CDCl₃) δ 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m, 2H), 7.99 (m, 2H), 8.58 (d, 1H).

Step E: Preparation of N-[4-Chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Step D (5.0 g, 11.3 mmol) in tetrahydrofuran (35 mL) was added dropwise isopropylamine (2.9 mL, 34.0 mmol) in tetrahydrofuran. (10 mL) at room temperature. The reaction mixture was then warmed until all solids had dissolved and stirred an additional five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel, followed by trituration with ether/hexane to afford the title compound, a compound of the present invention, as a solid (4.6 g), melting at 195-196° C.

¹H NMR. (CDCl₃) δ 1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95 (br d, 1H), 7.1-7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H), 8.50 (d, 1H), 10.24 (br s, 1H).

Example 7 Preparation of N-[4-Chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Example 6, Step D (4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 mL) was added methylamine (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid wag purified by chromatography on silica gel to afford 4.09 g of the title compound, a compound of the present invention, as a white solid melting at 185-186° C.

¹H NMR (DMSO-d₆) δ 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46 (dd, 1H), 7.65 (dd, 1H), 7.74 (s, 1H), 8.21 (d, 1H), 8.35 (br q, 1H), 8.74 (d, 1H), 10.39 (s, 1H).

Example 8 Preparation of 3-Chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide Step A: Preparation of 3-Chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyllithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below −65° C. Upon completion of the addition the reaction mixture was maintained at −78° C. for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at −78° C., warmed to −20° C. and then quenched with water (1 L), The reaction mixture was extracted with methylene chloride (4×500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product compound as a yellow oil (160 g).

¹H NMR (CDCl₃) δ 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, 1H).

Step B: Preparation of 3-Chloropyrazole

To trifluoroacetic acid (290 mL) was added dropwise the chloropyrazole product (160 g) from Step A, and the reaction mixture was stirred at room temperature for 1.5 hours and then concentrated at reduced pressure. The residue was taken up in hexane, insoluble solids were filtered off, and the hexane was concentrated to afford the crude product as an oil. The crude product was further purified by chromatography on silica gel using ether/hexane (40:60) as eluent to afford the title product as a yellow oil (64.44 g).

¹H NMR (CDCl₃) δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H).

Step C: Preparation of 3-Chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine

To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100° C. for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g).

¹H NMR (CDCl₃) δ 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09 (s, 1H), 8.41 (d, 1H).

Step D: Preparation of 3-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

To a solution of the pyrazole product from Step C (39.75 g, 186 mmol) in dry tetrahydrofuran (400 mL) at −78° C. was added dropwise a solution of 2.0 M lithium diisopropylamide (93 mL, 186 mmol) in tetrahydrofuran. Carbon dioxide was bubbled through the amber solution for 14 minutes, after which time the solution became pale brownish-yellow. The reaction was made basic with 1N aqueous sodium hydroxide solution and extracted with ether (2×500 mL). The aqueous extracts were acidified with 6 N hydrochloric acid and extracted with ethyl acetate (3×500 mL). The ethyl acetate extracts were dried over magnesium sulfate and concentrated to afford the title product as an off-white solid (42.96 g). (Product from another run following similar procedure melted at 198-199° C.)

¹H NMR (DMSO-d₆) δ 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51 (d, 1H).

Step E: Preparation of 6-Chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of the carboxylic acid product from Step D (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture was then stirred for 30 minutes at 0° C. Then, 2-amino-3-methyl-5-chlorobenzoic acid from Example 6, Step A (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10° C. The reaction mixture was stirred 60 minutes at 0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g).

¹H NMR (CDCl₃) δ 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (an, 2H), 7.98 (d, 2H), 8.56 (d, 1H).

Step F: Preparation of 3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Step E (6.21 g, 15.21 mmol) in tetrahydrofuran (100 mL) was added isopropylamine (4.23 g, 72.74 mmol) and the reaction mixture was then heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (5.05 g) melting at 173-175° C.

¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97 (d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83 (d, 1H), 8.43 (d, 1H), 10.15 (br s, 1H).

Example 9 Preparation of 3-Chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Example 8, Step E (6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine (2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture was heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (4.57 g) melting at 225-226° C.

¹H NMR (CDCl₃) δ 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, 1H), 7.06 (s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m, 1H), 7.83 (d, 1H), 8.42 (d, 1H), 10.08 (br s, 1H).

Example 10 Preparation of 3-Bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide Step A: Preparation of 3-Bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solution of n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintaining the temperature below −60° C. A thick solid formed during the addition. Upon completion of the addition the reaction mixture was maintained for an additional 15 minutes, after which time a solution of 1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150 mL) was added dropwise while maintaining the temperature below −70° C. The reaction mixture turned a clear orange; stirring was continued for an additional 15 minutes. The −78° C. bath was removed and the reaction was quenched with water (600 mL). The reaction mixture was extracted with methylene chloride (4×), and the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride/hexane (50:50) as eluent to afford the title product as a clear colorless oil (57.04 g).

¹H NMR (CDCl₃) δ 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

Step B: Preparation of 3-Bromopyrazole

To trifluoroacetic acid (70 mL) was slowly added the bromopyrazole product (57.04 g) from Step A. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated at reduced pressure. The residue was taken up in hexane, insoluble solids were filtered off, and the hexane was evaporated to afford the crude product as an oil. The crude product was further purified by chromatography on silica gel using ethyl acetate/dichloromethane (10:90) as eluent to afford an oil. The oil was taken up in dichloromethane, neutralized with aqueous sodium bicarbonate solution, extracted with methylene chloride (3×), dried over magnesium sulfate and concentrated to afford the title product as a white solid (25.9 g), m.p. 61-64° C.

¹H NMR (CDCl₃) δ 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H).

Step C: Preparation of 2-(3-Bromo-1H-pyrazol-1-yl)-3-chloropyridine

To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol.) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid filter cake was taken up in methylene chloride and washed sequentially with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without further purification in Step D.

¹H NMR (CDCl₃) δ 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05 (s, 1H), 8.43 (d, 1H).

Step D: Preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

To a solution of the pyrazole product from Step C (30.4 g, 118 mmol) in dry tetrahydrofuran (250 mL) at −76° C. was added dropwise a solution of lithium diisopropyl-amide (118 mmol) in tetrahydrofuran at such a rate as to maintain the temperature below −71° C. The reaction mixture was stirred for 15 minutes at −76° C., and carbon dioxide was then bubbled through for 10 minutes, causing warming to −57° C. The reaction mixture was warmed to −20° C. and quenched with water. The reaction mixture was concentrated and then taken up in water (1 L) and ether (500 mL), and then aqueous sodium hydroxide solution (1 N, 20 mL) was added. The aqueous extracts were washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered, washed with water and dried to afford the title product as a tan solid (27.7 g). (Product from another run following similar procedure melted at 200-201° C.)

¹H NMR (DMSO-d₆) δ 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d, 1H).

Step E: Preparation of 2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

A procedure analogous to that of Example 6, Step D was used to convert the pyrazolecarboxylic acid product from Example 10, Step D (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (0.92 g, 4.96 mmol) to the title product as a solid (1.21 g).

¹H NMR (CDCl₃) δ 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d, 1H), 8.04 (m, 1H), 8.25 (s, 1H), 8.26 (d, 1H).

Step F: Preparation of 3-Bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 mL, 1.42 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (150 mg), m.p. 159-161° C.

¹H NMR (CDCl₃) δ 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99 (m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41 (d, 1H).

Example 11 Preparation of 3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

To a solution of the benzoxazinone product of Example 10, Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (40 mg), m.p. 162-164° C.

¹H NMR (CDCl₃) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).

The following Example 12 illustrates an alternative preparation of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide and 3-chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, by further steps illustrated in Examples 8 and 9.

Example 12 Preparation of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid Step A: Preparation of Ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate)

A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 mL) and an ethanolic solution of sodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83° C. It was then treated with 3-chloro-2(1H)-pyridinone hydrazone (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28° C. The slurry was held at about 2° C. for 2 hours. The product was isolated via filtration, washed with aqueous ethanol (40%, 3×50 mL), and then air-dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by ¹H NMR.

¹H NMR (DMSO-d₆) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18 (s, 1H).

Step B: Preparation of Ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-chloro-2-pyrazoline-5-carboxylate)

To a 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged acetonitrile (1000 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (91.0 g, 0.337 mol) and phosphorus oxychloride (35.0 mL, 0.375 mol). Upon adding the phosphorus oxychloride, the mixture self-heated from 22 to 25° C. and a precipitate formed. The light-yellow slurry was heated to reflux at 83° C. over a period of 35 minutes, whereupon the precipitate dissolved. The resulting orange solution was held at reflux for 45 minutes, whereupon it had become black-green. The reflux condenser was replaced with a distillation head, and 650 mL of solvent was removed by distillation. A second 2-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (130 g, 1.55 mol) and water (400 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 15 minutes. The resulting, two-phase mixture was stirred vigorously for 20 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (250 mL) and then was stirred for 50 minutes. The mixture was treated with Celite® 545 diatomaceous earth filter aid (11 g) and then filtered to remove a black, tarry substance that inhibited phase separation. Since the filtrate was slow to separate into distinct phases, it was diluted with dichloromethane (200 mL) and water (200 mL) and treated with more Celite® 545 (15 g). The mixture was filtered, and the filtrate was transferred to a separatory funnel. The heavier, deep green organic layer was separated. A rag layer (50 mL) was refiltered and then added to the organic layer. The organic solution (800 mL) was treated with magnesium sulfate (30 g) and silica gel (12 g), and the slurry was stirred magnetically for 30 minutes. The slurry was filtered to remove the magnesium sulfate and silica gel, which had become deep blue-green. The filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated on a rotary evaporator. The product consisted of dark amber oil (92.0 g, 93% yield). The only appreciable impurities observed by ¹H NMR were 1% starting material and 0.7% acetonitrile.

¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H), 4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step C: Preparation of Ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylate)

A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitrile (1000 mL) and sulfuric acid (98%, 35.0 mL, 0.661 mol). The mixture self-heated from 22 to 35° C. upon adding the sulfuric acid. After being stirred for several minutes, the mixture was treated with potassium persulfate (140 g, 0.518 mol). The slurry was heated to reflux at 84° C. for 4.5 hours. The resulting orange slurry while still warm (50-65° C.) was filtered to remove a fine, white precipitate. The filter cake was washed with acetonitrile (50 mL). The filtrate was concentrated to about 500 mL on a rotary evaporator. A second 2-L four-necked flask equipped with a mechanical stirrer was charged with water (1250 mL). The concentrated reaction mass was added to the water over a period of about 5 minutes. The product was isolated via filtration, washed with aqueous acetonitrile (25%, 3×125 mL), washed once with water (100 mL), and then dried overnight in vacuo at room temperature. The product consisted of a crystalline, orange powder (79.3 g, 82% yield). The only appreciable impurities observed by ¹H NMR were about 1.9% water and 0.6% acetonitrile.

¹H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71 (dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H).

Step D: Preparation of 3-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternatively named 1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylic acid)

A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step C) (97.5% pure, 79.3 g, 0.270 mol), methanol (260 mL), water (140 mL) and sodium hydroxide pellets (13.0 g, 0.325 mol). Upon adding the sodium hydroxide the mixture self-heated from 22 to 35° C., and the starting material began to dissolve. After being stirred for 45 minutes under ambient conditions, all of the starting material had dissolved. The resulting deep orange-brown solution was concentrated to about 250 mL on a rotary evaporator. The concentrated reaction mixture was then diluted with water (400 mL). The aqueous solution was extracted with ether (200 mL). Then the aqueous layer was transferred to a 1-L Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol) over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2×200 mL), cover washed once with water (100 mL) and then air-dried on the filter for 1.5 hours. The product consisted of a crystalline, light brown powder (58.1 g, 83% yield). About 0.7% ether was the only appreciable impurity observed by ¹H NMR.

¹H NMR (DMSO-d₆) δ 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56 (d, 1H), 13.95 (br s, 1H).

The following Example 13 illustrates an alternative preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide and 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, by further steps illustrated in Examples 10 and 11.

Example 13 Preparation 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid Step A1: Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-bromo-2-pyrazoline-5-carboxylate) using phosphorus oxybromide

A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by ¹H NMR was 0.3% acetonitrile.

¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step A2: Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate using phosphorus pentabromide

A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (330 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (52.0 g, 0.193 mol), and phosphorus pentabromide (41.0 g, 0.0952 mol). The orange slurry was heated to reflux at 84° C. over a period of 20 minutes. The resulting brick-red mixture was held at reflux for 90 minutes, at which time a dense tan crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (220 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (40 g, 0.48 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting, two-phase mixture was stirred vigorously for 10 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 10 minutes. The mixture was treated with Celite® 545 diatomaceous filter aid (5 g) and then filtered to remove a purple, tarry substance. The filter cake was washed with dichloromethane (50 mL). The filtrate was transferred to a separatory funnel. The purple-red organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.2 g). The slurry was stirred magnetically for 40 minutes. The slurry was filtered to remove the magnesium sulfate and charcoal. The filtrate was concentrated on a rotary evaporator. The product consisted of a dark amber oil (61.2 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by ¹H NMR was 0.7% acetonitrile.

¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H), 4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step B: Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylate)

A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. the product of Steps A1 and A2) (40.2 g, 0.121 mol), acetonitrile (300 mL) and sulfuric acid (98%, 13.0 mL, 0.245 mol). The mixture self-heated from 22 to 36° C. upon adding the sulfuric acid. After being stirred for several minutes, the mixture was treated with potassium persulfate (48.0 g, 0.178 mol). The slurry was heated to reflux at 84° C. for 2 hours. The resulting orange slurry while still warm (50-65° C.) was filtered to remove a white precipitate. The filter cake was washed with acetonitrile (2×50 mL). The filtrate was concentrated to about 200 mL on a rotary evaporator. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with water (400 mL). The concentrated reaction mass was added to the water over a period of about 5 minutes. The product was isolated via filtration, washed sequentially with aqueous acetonitrile (20%, 100 mL) and water (75 mL), and was then air-dried on the filter for 1 hour. The product consisted of a crystalline, orange powder (36.6 g, 90% yield). The only appreciable impurities observed by ¹H NMR were about 1% of an unknown and 0.5% acetonitrile.

¹H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72 (dd, 1H), 8.39 (d, 1H), 8.59 (d, 1H).

Step C: Preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternatively named 1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic acid)

A 300-mL four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step B) (98.5% pure, 25.0 g, 0.0756 mol), methanol (75 mL), water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Upon adding the sodium hydroxide the mixture self-heated from 29 to 34° C. and the starting material began to dissolve. After being stirred for 90 minutes under ambient conditions, all of the starting material had dissolved. The resulting dark orange solution was concentrated to about 90 mL on a rotary evaporator. The concentrated reaction mixture was then diluted with water (160 mL). The aqueous solution was extracted with ether (100 mL). Then the aqueous layer was transferred to a 500-mL Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839 mol) over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2×40 mL), cover washed once with water (25 mL), and then air-dried on the filter for 2 hours. The product consisted of a crystalline, tan powder (20.9 g, 91% yield). The only appreciable impurities observed by ¹H NMR were about 0.8% of an unknown and 0.7% ether.

¹H NMR (DMSO-d₆) δ 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H).

The following Example 14 illustrates an alternative preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, which can be used to prepare, for example, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. product of Example 13, Step B).

Example 14 Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate from ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate using hydrogen bromide

Hydrogen bromide was passed through a solution of ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. product of Example 12, Step B) (8.45 g, 29.3 mmol) in dibromomethane (85 mL). After 90 minutes the gas flow was terminated, and the reaction mixture was washed with aqueous sodium bicarbonate solution (100 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (9.7 g, 99% yield), which crystallized on standing.

¹H NMR (CDCl₃) δ 1.19 (t, 3H), 3.24 (½ of AB in ABX pattern, J=9.3, 17.3 Hz, 1H), 3.44 (½ of AB in ABX pattern, J=11.7, 17.3 Hz, 1H), 4.18 (q, 2H), 5.25 (X of ABX, 1H, J=9.3, 11.9 Hz), 6.85 (dd, J=4.7, 7.7 Hz, 1H), 7.65 (dd, J=1.6, 7.8 Hz, 1H), 8.07 (dd, J=1.6, 4.8 Hz, 1H).

The following Example 15 illustrates the preparation of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate, which can be used to prepare ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate by procedures similar to that described in Example 14.

Example 15 Preparation of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3×70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100° C.

IR (nujol) ν 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 868, 845 cm⁻¹.

¹H NMR (CDCl₃) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (½ of AB in ABX pattern, J=17.3, 9 Hz, 1H), 3.33 (½ of AB in ABX pattern, J=17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (X of ABX, J=9, 11.8 Hz, 1H), 6.79 (dd, J=4.6, 7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.56 (dd, J=1.6, 7.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 8.01 (dd, J=1.4, 4.6 Hz, 1H).

Example 16 Preparation of N-[4-Chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide Step A: Preparation of Ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate

To a suspension of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. product of Example 12, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200 mL) was added sulfuric acid (20 g, 200 mmol) in one portion. The reaction mixture thinned to form a pale green, nearly clear solution before thickening again to form a pale yellow suspension. Potassium persulfate (33 g, 120 mmol) was added in one portion, and then the reaction mixture was heated at gentle reflux for 3.5 hours. After cooling using an ice bath, a precipitate of white solid was removed by filtration and discarded. The filtrate was diluted with water (400 mL) and then extracted three times with ethyl ether (700 mL total). Concentration of the combined ether extracts to a reduced volume (75 mL) caused precipitation of an off-white solid (3.75 g), which was collected by filtration. The ether mother liquor was further concentrated to yield a second crop of an off-white precipitate (4.2 g), which was also collected by filtration. An off-white solid also precipitated from the aqueous phase; this solid (4.5 g) was collected by filtration to provide a combined total of 12.45 g of the title compound.

¹H NMR (DMSO-d₆) δ 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6 (t, 1H), 8.19 (d, 8.5 (d, 1H), 10.6 (s, 1H).

Step B: Preparation of Ethyl 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate

To a suspension of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 15 minutes at 20° C. The stirred suspension was then cooled to 5° C., and 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated to reflux, at which time thin layer chromatography showed the reaction to be complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a pale yellow oil.

¹H NMR (CDCl₃) δ 1.21 (t, 3H), 4.20 (q, 2H), 4.63 (q, 2H), 6.53 (s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H).

Step C: Preparation of 1-(3-Chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid

To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate (i.e. product of Step B) (0.92 g, 2.8 mmol) in methanol (15 mL) was added water (5 mL), which caused the reaction mixture to become cloudy. An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes, during which time the reaction mixture became again clear. Water (20 mL) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 using concentrated hydrochloric acid and then extracted with ethyl acetate (50 mL). The ethyl acetate extract, which was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0.8 g).

¹H NMR (DMSO-d₆) δ 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d, 1H), 8.55 (d, 1H), 13.7 (bs, 1H).

Step D: Preparation of 6-Chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 6, Step A) (97 g, 520 mmol) stirred in dry dioxane (750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise. The reaction mixture exothermically warmed slowly to 42° C., and the solid almost completely dissolved before a thick suspension formed again. After the suspension was stirred at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether, and dried to yield the title product compound, obtained as a white solid (98 g).

¹H NMR (DMSO-d₆) δ 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 1H), 11.2 (s, 1H).

Step E: Preparation of 6-Chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

To a suspension of 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 g, 24 mmol) stirred in dichloromethane (100 mL) was added N,N-dimethylformamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over a period of 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The isolated acid chloride was dissolved in dry acetonitrile (10 mL) and added to a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of Step D) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10 mL) was added, and the solution heated at reflux 6 hours. After cooling using an ice bath, a precipitate of white solid (9.15 g) was collected. The ¹H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. A small portion of the collected precipitate was recrystallized from acetonitrile to yield the pure title product melting at 178-180° C.

¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7 (t, 1H), 7.75 (s, 1H), 7.9 (s, 1H), 8.3 (d, 1H), 8.6 (d, 1H).

Step F: Preparation of N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

To a suspension of the 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) in tetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 45 minutes. Thin layer chromatography then showed the reaction to be complete. Ethyl ether (100 mL) was added, and the reaction mixture was stirred for 2 hours while a precipitate formed. The precipitate was collected by filtration and then recrystallized from acetonitrile to yield a white solid (0.82 g). A second crop of white solid (0.35 g) precipitated from the acetonitrile mother liquor and was collected by filtration. The initial ether/tetrahydrofuran mother liquor was concentrated to dryness, and the residual solid was recrystallized from acetonitrile to yield a third crop of white solid (0.95 g). The three crops were combined, totaling 2.12 g (after drying) of the title compound, a compound of the present invention, isolated as a white solid, melting at 195-197° C.

¹H NMR (CDCl₃) δ 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15 (q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.8 (d, 1H), 8.45 (d, 1H), 10.0 (s, 1H).

The following Example 17 illustrates an alternative preparation of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 1-(3-chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, by further steps illustrated in Examples 4.

Example 17 Preparation of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid Step A: Preparation of 3-chloro-2(1H)-pyridinone (2,2,2-trifluoro-1-methylethylidene)hydrazone

1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to 3-chloro-2(1H)-pyridinone hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure and the mixture partitioned between ethyl acetate (100 mL) and saturated aqueous sodium carbonate solution (100 mL). The organic layer was dried and evaporated Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (after crystallization from ethyl acetate/hexanes).

IR (nujol) ν 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196, 1158, 1100, 1032, 992, 800 cm⁻¹.

¹H NMR. (CDCl₃) δ 2.12 (s, 3H), 6.91-6.86 (m, 1H), 7.64-7.61 (m, 1H), 8.33-8.32 (m, 2H). MS m/z 237 (M⁺).

Step B: Preparation of ethyl hydrogen ethanedioate (3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazide (alternatively named ethyl hydrogen ethanedioate (3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazine)

Triethylamine (20.81 g, 0.206 mol) was added to 3-chloro-2(1H)-pyridinone (2,2,2-trifluoro-1-methylethylidene)hydrazone (i.e. the product of Step A) (32.63 g, 0.137 mol) in dichloromethane (68 mL) at 0° C. Ethyl chlorooxoacetate (18.75 g, 0.137 mol) in dichloromethane (69 mL) was added dropwise to the mixture at 0° C. The mixture was allowed to warm to 25° C. over about 2 hours. The mixture was cooled to 0° C. and a further portion of ethyl chlorooxoacetate (3.75 g, 27.47 mmol) in dichloromethane (14 mL) was added dropwise. After about an additional 1 hour, the mixture was diluted with dichloromethane (about 450 mL), and the mixture was washed with water (2×150 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with 1:1 ethyl acetate-hexanes) gave the product as a solid (42.06 g, 90% yield), imp. 73.0-73.5° C. (after crystallization from ethyl acetate/hexanes).

IR (nujol) ν 1751, 1720, 1664, 1572, 1417, 1361, 1330, 1202, 1214, 1184, 1137, 1110, 1004, 1043, 1013, 942, 807, 836 cm⁻¹.

¹H NMR (DMSO-d₆, 115° C.) 1.19 (t, 3H), 1.72 (br s, 3H), 4.25 (q, 2H), 7.65 (dd, J=8.3, 4.7 Hz, 1H), 8.20 (dd, J=7.6, 1.5 Hz, 1H), 8.55 (d, J=3.6 Hz, 1H).

MS m/z 337 (M⁺).

Step C: Preparation of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

Ethyl hydrogen ethanedioate (3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methyl-ethylidene)hydrazide (i.e. the product of Step B) (5 g, 14.8 mmol) in dimethyl sulfoxide (25 mL) was added to tetrabutylammonium fluoride hydrate (10 g) in dimethyl sulfoxide (25 mL) over 8 hours. When the addition was complete, the mixture was poured into acetic acid (3.25 g) in water (25 mL). After stifling at 25° C. overnight, the mixture was then extracted with toluene (4×25 mL), and the combined toluene extracts were washed with water (50 mL), dried and evaporated to give a solid. Chromatography on silica gel (eluted with 1:2 ethyl acetate-hexanes) gave the product as a solid (2.91 g, 50% yield, containing about 5% of 3-chloro-2(1H)-pyridinone (2,2,2-trifluoro-1-methylethylidene)hydrazone), m.p. 78-78.5° C. (after recrystallization from ethyl acetate/hexanes).

IR (nujol) ν 3403, 1726, 1618, 1582, 1407, 1320, 1293, 1260, 1217, 1187, 1150, 1122, 1100, 1067, 1013, 873, 829 cm⁻¹.

¹H NMR (CDCl₃) δ 1.19 (s, 3H), 3.20 (½ of ABZ pattern, J=18 Hz, 1H), 3.42 (½ of ABZ pattern, J=18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, J=7.9, 4.9 Hz, 1H), 7.74 (dd, J=7.7, 1.5 Hz, 1H), 8.03 (dd, J=4.7, 1.5 Hz, 1H).

MS m/z 319 (M⁺).

Step D: Preparation of ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

Sulfuric acid (concentrated, 2 drops) was added to ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) and the mixture was warmed to 65° C. for about 1 hour. The mixture was allowed to cool to 25° C. and most of the acetic acid was removed under reduced pressure. The mixture was partitioned between saturated aqueous sodium carbonate solution (100 mL) and ethyl acetate (100 mL). The aqueous layer was further extracted with ethyl acetate (100 mL). The combined organic extracts were dried and evaporated to give the product as an oil (0.66 g, 77% yield).

IR (neat) ν 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277, 1236, 1135, 1082, 1031, 973, 842, 802 cm⁻¹.

¹H NMR (CDCl₁) δ 1.23 (t, 3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd, J=8.1, 4.7 Hz, 1H), 7.94 (dd, J=6.6, 2 Hz, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H).

MS m/z 319 (M⁺).

Step E: Preparation of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was acidified with concentrated hydrochloric acid and was extracted with ethyl acetate (3×20 mL). The combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), m.p. 178-179° C. (after crystallization from hexanes-ethyl acetate).

IR (nujol) ν 1711, 1586, 1565, 1550, 1440, 1425, 1292, 1247, 1219, 1170, 1135, 1087, 1059, 1031, 972, 843, 816 cm⁻¹.

¹H NMR (DMSO-d₅) δ 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H).

Examples 18 and 19 illustrate alternatives to reaction conditions described in Example 10, Step E and Example 8, Step E, respectively.

Example 18 Preparation of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 10, Step D) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 6 Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over 5 minutes at a temperature of −5 to 0° C. The reaction mixture was stirred 15 minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.

¹H NMR (DMSO-d₆) δ 1.72 (s, 3H) 7.52 (s, 1H), 7.72-7.78 (m, 2H), 7.88 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

Example 19 Preparation of 6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 6, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h, Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.

¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H), 7.87 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

By the procedures described herein together with methods known in the art, the following compounds of Table 1 can be prepared. The following abbreviations are used in the Tables which follow: t means tertiary, s means secondary, n means normal, i means iso, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl, and Bu means butyl.

TABLE 1

R³ R⁴ Q X Y Z R³ R⁴ Q X Y Z i-Pr Me NMe N CH CCF₃ i-Pr Me NMe N CH CC₂F₅ i-Pr Cl NMe N CH CCF₃ i-Pr Cl NMe N CH CC₂F₅ i-Pr Br NMe N CH CCF₃ i-Pr Br NMe N CH CC₂F₅ i-Pr I NMe N CH CCF₃ i-Pr I NMe N CH CC₂F₅ i-Pr F NMe N CH CCF₃ i-Pr F NMe N CH CC₂F₅ i-Pr H NMe N CH CCF₃ i-Pr H NMe N CH CC₂F₅ i-Pr Et NMe N CH CCF₃ i-Pr Et NMe N CH CC₂F₅ i-Pr Me NEt N CH CCF₃ t-Bu Me NMe N CH CCF₃ i-Pr Cl NEt N CH CCF₃ t-Bu Cl NMe N CH CCF₃ i-Pr Br NEt N CH CCF₃ t-Bu Br NMe N CH CCF₃ i-Pr I NEt N CH CCF₃ t-Bu I NMe N CH CCF₃ i-Pr F NEt N CH CCF₃ t-Bu F NMe N CH CCF₃ i-Pr H NEt N CH CCF₃ t-Bu H NMe N CH CCF₃ i-Pr Et NEt N CH CCF₃ t-Bu Et NMe N CH CCF₃

TABLE 2

W X Y Z R³ R⁴ R⁶ R⁹ CH CH CH CH i-Pr Me CF₃ Me CH CH CH CH t-Bu Me CF₃ Me CH CH CH CH i-Pr Cl CF₃ Me CH CH CH CH t-Bu Cl CF₃ Me CH CH CH CH i-Pr Br CF₃ Me CH CH CH CH t-Bu Br CF₃ Me CH CH CH CH i-Pr Me Cl Me CH CH CH CH t-Bu Me Cl Me CH CH CH CH i-Pr Cl Cl Me CH CH CH CH t-Bu Cl Cl Me CH CH CH CH i-Pr Br Cl Me CH CH CH CH t-Bu Br Cl Me CH CH CH CH i-Pr Me Br Me CH CH CH CH t-Bu Me Br Me CH CH CH CH i-Pr Cl Br Me CH CH CH CH t-Bu Cl Br Me CH CH CH CH i-Pr Br Br Me CH CH CH CH t-Bu Br Br Me CH CH CH CH i-Pr Me CN Me CH CH CH CH t-Bu Me CN Me CH CH CH CH i-Pr Cl CN Me CH CH CH CH t-Bu Cl CN Me CH CH CH CH i-Pr Br CN Me CH CH CH CH t-Bu Br CN Me CH CH CH CH i-Pr Me CF₃ F CH CH CH CH t-Bu Me CF₃ F CH CH CH CH i-Pr Cl CF₃ F CH CH CH CH t-Bu Cl CF₃ F CH CH CH CH i-Pr Br CF₃ F CH CH CH CH t-Bu Br CF₃ F CH CH CH CH i-Pr Me Cl F CH CH CH CH t-Bu Me Cl F CH CH CH CH i-Pr Cl Cl F CH CH CH CH t-Bu Cl Cl F CH CH CH CH i-Pr Br Cl F CH CH CH CH t-Bu Br Cl F CH CH CH CH i-Pr Me Br F CH CH CH CH t-Bu Me Br F CH CH CH CH i-Pr Cl Br F CH CH CH CH t-Bu Cl Br F CH CH CH CH i-Pr Br Br F CH CH CH CH t-Bu Br Br F CH CH CH CH i-Pr Me CN F CH CH CH CH t-Bu Me CN F CH CH CH CH i-Pr Cl CN F CH CH CH CH t-Bu Cl CN F CH CH CH CH i-Pr Br CN F CH CH CH CH t-Bu Br CN F CH CH CH CH i-Pr Me CF₃ Cl CH CH CH CH t-Bu Me CF₃ Cl CH CH CH CH i-Pr Cl CF₃ Cl CH CH CH CH t-Bu Cl CF₃ Cl CH CH CH CH i-Pr Br CF₃ Cl CH CH CH CH t-Bu Br CF₃ Cl CH CH CH CH i-Pr Me Cl Cl CH CH CH CH t-Bu Me Cl Cl CH CH CH CH i-Pr Cl Cl Cl CH CH CH CH t-Bu Cl Cl Cl CH CH CH CH i-Pr Br Cl Cl CH CH CH CH t-Bu Br Cl Cl CH CH CH CH i-Pr Me Br Cl CH CH CH CH t-Bu Me Br Cl CH CH CH CH i-Pr Cl Br Cl CH CH CH CH t-Bu Cl Br Cl CH CH CH CH i-Pr Br Br Cl CH CH CH CH t-Bu Br Br Cl CH CH CH CH i-Pr Me CN Cl CH CH CH CH t-Bu Me CN Cl CH CH CH CH i-Pr Cl CN Cl CH CH CH CH t-Bu Cl CN Cl CH CH CH CH i-Pr Br CN Cl CH CH CH CH t-Bu Br CN Cl CH CH CH CH i-Pr Me CF₃ Br CH CH CH CH t-Bu Me CF₃ Br CH CH CH CH i-Pr Cl CF₃ Br CH CH CH CH t-Bu Cl CF₃ Br CH CH CH CH i-Pr Br CF₃ Br CH CH CH CH t-Bu Br CF₃ Br CH CH CH CH i-Pr Me Cl Br CH CH CH CH t-Bu Me Cl Br CH CH CH CH i-Pr Cl Cl Br CH CH CH CH t-Bu Cl Cl Br CH CH CH CH i-Pr Br Cl Br CH CH CH CH t-Bu Br Cl Br CH CH CH CH i-Pr Me Br Br CH CH CH CH t-Bu Me Br Br CH CH CH CH i-Pr Cl Br Br CH CH CH CH t-Bu Cl Br Br CH CH CH CH i-Pr Br Br Br CH CH CH CH t-Bu Br Br Br CH CH CH CH i-Pr Me CN Br CH CH CH CH t-Bu Me CN Br CH CH CH CH i-Pr Cl CN Br CH CH CH CH t-Bu Cl CN Br CH CH CH CH i-Pr Br CN Br CH CH CH CH t-Bu Br CN Br CH CH CH CH i-Pr Me CF₃ CN CH CH CH CH t-Bu Me CF₃ CN CH CH CH CH i-Pr Cl CF₃ CN CH CH CH CH t-Bu Cl CF₃ CN CH CH CH CH i-Pr Br CF₃ CN CH CH CH CH t-Bu Br CF₃ CN CH CH CH CH i-Pr Me Cl CN CH CH CH CH t-Bu Me Cl CN CH CH CH CH i-Pr Cl Cl CN CH CH CH CH t-Bu Cl Cl CN CH CH CH CH i-Pr Br Cl CN CH CH CH CH t-Bu Br Cl CN CH CH CH CH i-Pr Me Br CN CH CH CH CH t-Bu Me Br CN CH CH CH CH i-Pr Cl Br CN CH CH CH CH t-Bu Cl Br CN CH CH CH CH i-Pr Br Br CN CH CH CH CH t-Bu Br Br CN CH CH CH 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CH CH CH N i-Pr Br Cl F CH CH CH N t-Bu Br Cl F CH CH CH N i-Pr Me Br F CH CH CH N t-Bu Me Br F CH CH CH N i-Pr Cl Br F CH CH CH N t-Bu Cl Br F CH CH CH N i-Pr Br Br F CH CH CH N t-Bu Br Br F CH CH CH N i-Pr Me CN F CH CH CH N t-Bu Me CN F CH CH CH N i-Pr Cl CN F CH CH CH N t-Bu Cl CN F CH CH CH N i-Pr Br CN F CH CH CH N t-Bu Br CN F CH CH CH N i-Pr Me CF₃ Cl CH CH CH N t-Bu Me CF₃ Cl CH CH CH N i-Pr Cl CF₃ Cl CH CH CH N t-Bu Cl CF₃ Cl CH CH CH N i-Pr Br CF₃ Cl CH CH CH N t-Bu Br CF₃ Cl CH CH CH N i-Pr Me Cl Cl CH CH CH N t-Bu Me Cl Cl CH CH CH N i-Pr Cl Cl Cl CH CH CH N t-Bu Cl Cl Cl CH CH CH N i-Pr Br Cl Cl CH CH CH N t-Bu Br Cl Cl CH CH CH N i-Pr Me Br Cl CH CH CH N t-Bu Me Br Cl CH CH CH N i-Pr Cl Br Cl CH CH CH N t-Bu Cl Br Cl CH CH CH N i-Pr Br Br Cl CH CH CH N t-Bu Br Br Cl CH CH CH N i-Pr Me CN Cl CH CH CH N t-Bu Me CN Cl CH CH CH N i-Pr Cl CN Cl CH CH CH N t-Bu Cl CN Cl CH CH CH N i-Pr Br CN Cl CH CH CH N t-Bu Br CN Cl CH CH CH N i-Pr Me CF₃ Br CH CH CH N t-Bu Me CF₃ Br CH CH CH N i-Pr Cl CF₃ Br CH CH CH N t-Bu Cl CF₃ Br CH CH CH N i-Pr Br CF₃ Br CH CH CH N t-Bu Br CF₃ Br CH CH CH N i-Pr Me Cl Br CH CH CH N t-Bu Me Cl Br CH CH CH N i-Pr Cl Cl Br CH CH CH N t-Bu Cl Cl Br CH CH CH N i-Pr Br Cl Br CH CH CH N t-Bu Br Cl Br CH CH CH N i-Pr Me Br Br CH CH CH N t-Bu Me Br Br CH CH CH N i-Pr Cl Br Br CH CH CH N t-Bu Cl Br Br CH CH CH N i-Pr Br Br Br CH CH CH N t-Bu Br Br Br CH CH CH N i-Pr Me CN Br CH CH CH N t-Bu Me CN Br CH CH CH N i-Pr Cl CN Br CH CH CH N t-Bu Cl CN Br CH CH CH N i-Pr Br CN Br CH CH CH N t-Bu Br CN Br CH CH CH N i-Pr Me CF₃ CN CH CH CH N t-Bu Me CF₃ CN CH CH CH N i-Pr Cl CF₃ CN CH CH CH N t-Bu Cl CF₃ CN CH CH CH N i-Pr Br CF₃ CN CH CH CH N t-Bu Br CF₃ CN CH CH CH N i-Pr Me Cl CN CH CH CH N t-Bu Me Cl CN CH CH CH N i-Pr Cl Cl CN CH CH CH N t-Bu Cl Cl CN CH CH CH N i-Pr Br Cl CN CH CH CH N t-Bu Br Cl CN CH CH CH N i-Pr Me Br CN CH CH CH N t-Bu Me Br CN CH CH CH N i-Pr Cl Br CN CH CH CH N t-Bu Cl Br CN CH CH CH N i-Pr Br Br CN CH CH CH N t-Bu Br Br CN CH CH CH N i-Pr Me CN CN CH CH CH N t-Bu Me CN CN CH CH CH N i-Pr Cl CN CN CH CH CH N t-Bu Cl CN CN CH CH CH N i-Pr Br CN CN CH CH CH N t-Bu Br CN CN CH CH CH CH Me Me CF₃ F CH CH CH CH Et Me CF₃ F CH CH CH CH CH(CH₃)CH₂OCH₃ Me CF₃ F CH CH CH CH CH(CH₃)CH₂SCH₃ Me CF₃ F CH CH CH CH propargyl Me CF₃ F CH CH CH CH Me Me CF₃ Cl CH CH CH CH Et Me CF₃ Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Me CF₃ Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Me CF₃ Cl CH CH CH CH propargyl Me CF₃ Cl CH CH CH CH Me Me Br F CH CH CH CH Et Me Br F CH CH CH CH CH(CH₃)CH₂OCH₃ Me Br F CH CH CH CH CH(CH₃)CH₂SCH₃ Me Br F CH CH CH CH propargyl Me Br F CH CH CH CH Me Me Br Cl CH CH CH CH Et Me Br Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Me Br Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Me Br Cl CH CH CH CH propargyl Me Br Cl CH CH CH CH Me Cl CF₃ F CH CH CH CH Et Cl CF₃ F CH CH CH CH CH(CH₃)CH₂OCH₃ Cl CF₃ F CH CH CH CH CH(CH₃)CH₂SCH₃ Cl CF₃ F CH CH CH CH propargyl Cl CF₃ F CH CH CH CH Me Cl CF₃ Cl CH CH CH CH Et Cl CF₃ Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Cl CF₃ Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Cl CF₃ Cl CH CH CH CH propargyl Cl CF₃ Cl CH CH CH CH Me Cl Br F CH CH CH CH Et Cl Br F CH CH CH CH CH(CH₃)CH₂OCH₃ Cl Br F CH CH CH CH CH(CH₃)CH₂SCH₃ Cl Br F CH CH CH CH propargyl Cl Br F CH CH CH CH Me Cl Br Cl CH CH CH CH Et Cl Br Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Cl Br Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Cl Br Cl CH CH CH CH propargyl Cl Br Cl CH CH CH N Me Me CF₃ F CH CH CH N Et Me CF₃ F CH CH CH N CH(CH₃)CH₂OCH₃ Me CF₃ F CH CH CH N CH(CH₃)CH₂SCH₃ Me CF₃ F CH CH CH N propargyl Me CF₃ F CH CH CH N Me Me CF₃ Cl CH CH CH N Et Me CF₃ Cl CH CH CH N CH(CH₃)CH₂OCH₃ Me CF₃ Cl CH CH CH N CH(CH₃)CH₂SCH₃ Me CF₃ Cl CH CH CH N propargyl Me CF₃ Cl CH CH CH N Me Me Br F CH CH CH N Et Me Br F CH CH CH N CH(CH₃)CH₂OCH₃ Me Br F CH CH CH N CH(CH₃)CH₂SCH₃ Me Br F CH CH CH N propargyl Me Br F CH CH CH N Me Me Br Cl CH CH CH N Et Me Br Cl CH CH CH N CH(CH₃)CH₂OCH₃ Me Br Cl CH CH CH N CH(CH₃)CH₂SCH₃ Me Br Cl CH CH CH N propargyl Me Br Cl CH CH CH N Me Cl CF₃ F CH CH CH N Et Cl CF₃ F CH CH CH N CH(CH₃)CH₂OCH₃ Cl CF₃ F CH CH CH N CH(CH₃)CH₂SCH₃ Cl CF₃ F CH CH CH N propargyl Cl CF₃ F CH CH CH N Me Cl CF₃ Cl CH CH CH N Et Cl CF₃ Cl CH CH CH N CH(CH₃)CH₂OCH₃ Cl CF₃ Cl CH CH CH N CH(CH₃)CH₂SCH₃ Cl CF₃ Cl CH CH CH N propargyl Cl CF₃ Cl CH CH CH N Me Cl Br F CH CH CH N Et Cl Br F CH CH CH N CH(CH₃)CH₂OCH₃ Cl Br F CH CH CH N CH(CH₃)CH₂SCH₃ Cl Br F CH CH CH N propargyl Cl Br F CH CH CH N Me Cl Br Cl CH CH CH N Et Cl Br Cl CH CH CH N CH(CH₃)CH₂OCH₃ Cl Br Cl CH CH CH N CH(CH₃)CH₂SCH₃ Cl Br Cl CH CH CH N propargyl Cl Br Cl C—Cl CH CH CH i-Pr Me CF₃ Cl C—F CH CH CH i-Pr Me CF₃ F CH CH CH CH i-Pr Me CF₃ ethynyl CH CH CH CH i-Pr Me CF₃ I CH CH CH CH i-Pr Me CF₃ SO₂Me C—Cl CH CH CH i-Pr Cl CF₃ Cl C—F CH CH CH i-Pr Cl CF₃ F CH CH CH CH i-Pr Cl CF₃ ethynyl CH CH CH CH i-Pr Cl CF₃ I CH CH CH CH i-Pr Cl CF₃ SO₂Me C—Cl CH CH CH i-Pr Me Br Cl C—F CH CH CH i-Pr Me Br F CH CH CH CH i-Pr Me Br ethynyl CH CH CH CH i-Pr Me Br I CH CH CH CH i-Pr Me Br SO₂Me C—Cl CH CH CH i-Pr Cl Br Cl C—F CH CH CH i-Pr Cl Br F CH CH CH CH i-Pr Cl Br ethynyl CH CH CH CH i-Pr Cl Br I CH CH CH CH i-Pr Cl Br SO₂Me C—Cl CH CH N i-Pr Me CF₃ Cl C—F CH CH N i-Pr Me CF₃ F CH CH CH N i-Pr Me CF₃ ethynyl CH CH CH N i-Pr Me CF₃ I CH CH CH N i-Pr Me CF₃ SO₂Me C—Cl CH CH N i-Pr Cl CF₃ Cl C—F CH CH N i-Pr Cl CF₃ F CH CH CH N i-Pr Cl CF₃ ethynyl CH CH CH N i-Pr Cl CF₃ I CH CH CH N i-Pr Cl CF₃ SO₂Me C—Cl CH CH N i-Pr Me Br Cl C—F CH CH N i-Pr Me Br F CH CH CH N i-Pr Me Br ethynyl CH CH CH N i-Pr Me Br I CH CH CH N i-Pr Me Br SO₂Me C—Cl CH CH N i-Pr Cl Br Cl C—F CH CH N i-Pr Cl Br F CH CH CH N i-Pr Cl Br ethynyl CH CH CH N i-Pr Cl Br I CH CH CH N i-Pr Cl Br SO₂Me CH N CH N i-Pr Me CF₃ H CH N CH N i-Pr Me CF₃ Me CH N CH N i-Pr Me CF₃ Cl CH N CH N i-Pr Cl CF₃ H CH N CH N i-Pr Cl CF₃ Me CH N CH N i-Pr Cl CF₃ Cl CH N CH N i-Pr Me CN H CH N CH N i-Pr Me CN Me CH N CH N i-Pr Me CN Cl CH N CH N i-Pr Cl CN H CH N CH N i-Pr Cl CN Me CH N CH N i-Pr Cl CN Cl CH N CH N i-Pr Me Br H CH N CH N i-Pr Me Br Me CH N CH N i-Pr Me Br Cl CH N CH N i-Pr Cl Br B CH N CH N i-Pr Cl Br Me CH N CH N i-Pr Cl Br Cl CH N CH N t-Bu Me CF₃ H CH N CH N t-Bu Me CF₃ Me CH N CH N t-Bu Me CF₃ Cl CH N CH N t-Bu Cl CF₃ H CH N CH N t-Bu Cl CF₃ Me CH N CH N t-Bu Cl CF₃ Cl CH N CH N t-Bu Me CN H CH N CH N t-Bu Me CN Me CH N CH N t-Bu Me CN Cl CH N CH N t-Bu Cl CN H CH N CH N t-Bu Cl CN Me CH N CH N t-Bu Cl CN Cl CH N CH N t-Bu Me Br H CH N CH N t-Bu Me Br Me CH N CH N t-Bu Me Br Cl CH N CH N t-Bu Cl Br H CH N CH N t-Bu Cl Br Me CH N CH N t-Bu Cl Br Cl CH CH N N i-Pr Me CF₃ H CH CH N N i-Pr Me CF₃ Me CH CH N N i-Pr Me CF₃ Cl CH CH N N i-Pr Cl CF₃ H CH CH N N i-Pr Cl CF₃ Me CH CH N N i-Pr Cl CF₃ Cl CH CH N N i-Pr Me CN H CH CH N N i-Pr Me CN Me CH CH N N i-Pr Me CN Cl CH CH N N i-Pr Cl CN H CH CH N N i-Pr Cl CN Me CH CH N N i-Pr Cl CN Cl CH CH N N i-Pr Me Br H CH CH N N i-Pr Me Br Me CH CH N N i-Pr Me Br Cl CH CH N N i-Pr Cl Br H CH CH N N i-Pr Cl Br Me CH CH N N i-Pr Cl Br Cl CH CH N N i-Pr Me CF₃ H CH CH N N i-Pr Me CF₃ Me CH CH N N i-Pr Me CF₃ Cl CH CH N N i-Pr Cl CF₃ H CH CH N N i-Pr Cl CF₃ Me CH CH N N i-Pr Cl CF₃ Cl CH CH N N i-Pr Me CN H CH CH N N i-Pr Me CN Me CH CH N N i-Pr Me CN Cl CH CH N N i-Pr Cl CN H CH CH N N i-Pr Cl CN Me CH CH N N i-Pr Cl CN Cl CH CH N N i-Pr Me Br H CH CH N N i-Pr Me Br Me CH CH N N i-Pr Me Br Cl CH CH N N i-Pr Cl Br H CH CH N N i-Pr Cl Br Me CH CH N N i-Pr Cl Br Cl

TABLE 3

R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) Me CF₃ i-Pr Me H H Me CF₃ t-Bu Me H H Me CF₃ i-Pr Me H Me Me CF₃ t-Bu Me H Me Me CF₃ i-Pr Me Cl H Me CF₃ t-Bu Me Cl H Me CF₃ i-Pr Me Cl Me Me CF₃ t-Bu Me Cl Me Me CF₃ i-Pr Me Me Me Me CF₃ t-Bu Me Me Me Cl CF₃ i-Pr Me H H Cl CF₃ t-Bu Me H H Cl CF₃ i-Pr Me H Me Cl CF₃ t-Bu Me H Me Cl CF₃ i-Pr Me Cl H Cl CF₃ t-Bu Me Cl H Cl CF₃ i-Pr Me Cl Me Cl CF₃ t-Bu Me Cl Me Cl CF₃ i-Pr Me Me Me Cl CF₃ t-Bu Me Me Me

TABLE 4

R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) Me CF₃ i-Pr Me H Me Me CF₃ t-Bu Me H Me Me CF₃ i-Pr Me Me Me Me CF₃ t-Bu Me Me Me Me CF₃ i-Pr Cl H Me Me CF₃ t-Bu Cl H Me Me CF₃ i-Pr Cl Me Me Me CF₃ t-Bu Cl Me Me Cl CF₃ i-Pr Me H Me Cl CF₃ t-Bu Me H Me Cl CF₃ i-Pr Me Me Me Cl CF₃ t-Bu Me Me Me Cl CF₃ i-Pr Cl H Me Cl CF₃ t-Bu Cl H Me Cl CF₃ i-Pr Cl Me Me Cl CF₃ t-Bu Cl Me Me

TABLE 5

R⁴ R⁵ R⁶ R³ R⁹ R⁴ R⁵ R⁶ R³ R⁹ CH₃ F CF₃ Me Cl Cl Br Cl Me Br CH₃ F CF₃ Et Cl Cl Br Cl Et Br CH₃ F CF₃ i-Pr Cl Cl Br Cl i-Pr Br CH₃ F CF₃ t-Bu Cl Cl Br Cl t-Bu Br CH₃ F CF₃ Me Br Cl Br Br Me Cl CH₃ F CF₃ Et Br Cl Br Br Et Cl CH₃ F CF₃ i-Pr Br Cl Br Br i-Pr Cl CH₃ F CF₃ t-Bu Br Cl Br Br t-Bu Cl CH₃ F Cl Me Cl Cl Br Br Me Br CH₃ F Cl Et Cl Cl Br Br Et Br CH₃ F Cl i-Pr Cl Cl Br Br i-Pr Br CH₃ F Cl t-Bu Cl Cl Br Br t-Bu Br CH₃ F Cl Me Br Cl I CF₃ Me Cl CH₃ F Cl Et Br Cl I CF₃ Et Cl CH₃ F Cl i-Pr Br Cl I CF₃ i-Pr Cl CH₃ F Cl t-Bu Br Cl I CF₃ t-Bu Cl CH₃ F Br Me Cl Cl I CF₃ Me Br CH₃ F Br Et Cl Cl I CF₃ Et Br CH₃ F Br i-Pr Cl Cl I CF₃ i-Pr Br CH₃ F Br t-Bu Cl Cl I CF₃ t-Bu Br CH₃ F Br Me Br Cl I Cl Me Cl CH₃ F Br Et Br Cl I Cl Et Cl CH₃ F Br i-Pr Br Cl I Cl i-Pr Cl CH₃ F Br t-Bu Br Cl I Cl t-Bu Cl CH₃ Cl CF₃ Me Cl Cl I Cl Me Br CH₃ Cl CF₃ Et Cl Cl I Cl Et Br CH₃ Cl CF₃ i-Pr Cl Cl I Cl i-Pr Br CH₃ Cl CF₃ t-Bu Cl Cl I Cl t-Bu Br CH₃ Cl CF₃ Me Br Cl I Br Me Cl CH₃ Cl CF₃ Et Br Cl I Br Et Cl CH₃ Cl CF₃ i-Pr Br Cl I Br i-Pr Cl CH₃ Cl CF₃ t-Bu Br Cl I Br t-Bu Cl CH₃ Cl Cl Me Cl Cl I Br Me Br CH₃ Cl Cl Et Cl Cl I Br Et Br CH₃ Cl Cl i-Pr Cl Cl I Br i-Pr Br CH₃ Cl Cl t-Bu Cl Cl I Br t-Bu Br CH₃ Cl Cl Me Br Cl CF₃ CF₃ Me Cl CH₃ Cl Cl Et Br Cl CF₃ CF₃ Et Cl CH₃ Cl Cl i-Pr Br Cl CF₃ CF₃ i-Pr Cl CH₃ Cl Cl t-Bu Br Cl CF₃ CF₃ t-Bu Cl CH₃ Cl Br Me Cl Cl CF₃ CF₃ Me Br CH₃ Cl Br Et Cl Cl CF₃ CF₃ Et Br CH₃ Cl Br i-Pr Cl Cl CF₃ CF₃ i-Pr Br CH₃ Cl Br t-Bu Cl Cl CF₃ CF₃ t-Bu Br CH₃ Cl Br Me Br Cl CF₃ Cl Me Cl CH₃ Cl Br Et Br Cl CF₃ Cl Et Cl CH₃ Cl Br i-Pr Br Cl CF₃ Cl i-Pr Cl CH₃ Cl Br t-Bu Br Cl CF₃ Cl t-Bu Cl CH₃ Br CF₃ Me Cl Cl CF₃ Cl Me Br CH₃ Br CF₃ Et Cl Cl CF₃ Cl Et Br CH₃ Br CF₃ i-Pr Cl Cl CF₃ Cl i-Pr Br CH₃ Br CF₃ t-Bu Cl Cl CF₃ Cl t-Bu Br CH₃ Br CF₃ Me Br Cl CF₃ Br Me Cl CH₃ Br CF₃ Et Br Cl CF₃ Br Et Cl CH₃ Br CF₃ i-Pr Br Cl CF₃ Br i-Pr Cl CH₃ Br CF₃ t-Bu Br Cl CF₃ Br t-Bu Cl CH₃ Br Cl Me Cl Cl CF₃ Br Me Br CH₃ Br Cl Et Cl Cl CF₃ Br Et Br CH₃ Br Cl i-Pr Cl Cl CF₃ Br i-Pr Br CH₃ Br Cl t-Bu Cl Cl CF₃ Br t-Bu Br CH₃ Br Cl Me Br Cl Cl Cl n-Pr Cl CH₃ Br Cl Et Br Cl Cl Cl n-Bu Cl CH₃ Br Cl i-Pr Br Cl Cl Cl s-Bu Cl CH₃ Br Cl t-Bu Br Cl Cl Cl i-Bu Cl CH₃ Br Br Me Cl Br F CF₃ Me Cl CH₃ Br Br Et Cl Br F CF₃ Et Cl CH₃ Br Br i-Pr Cl Br F CF₃ i-Pr Cl CH₃ Br Br t-Bu Cl Br F CF₃ t-Bu Cl CH₃ Br Br Me Br Br F CF₃ Me Br CH₃ Br Br Et Br Br F CF₃ Et Br CH₃ Br Br i-Pr Br Br F CF₃ i-Pr Br CH₃ Br Br t-Bu Br Br F CF₃ t-Bu Br CH₃ I CF₃ Me Cl Br F Cl Me Cl CH₃ I CF₃ Et Cl Br F Cl Et Cl CH₃ I CF₃ i-Pr Cl Br F Cl i-Pr Cl CH₃ I CF₃ t-Bu Cl Br F Cl i-Bu Cl CH₃ I CF₃ Me Br Br F Cl Me Br CH₃ I CF₃ Et Br Br F Cl Et Br CH₃ I CF₃ i-Pr Br Br F Cl i-Pr Br CH₃ I CF₃ t-Bu Br Br F Cl t-Bu Br CH₃ I Cl Me Cl Br F Br Me Cl CH₃ I Cl Et Cl Br F Br Et Cl CH₃ I Cl i-Pr Cl Br F Br i-Pr Cl CH₃ I Cl t-Bu Cl Br F Br t-Bu Cl CH₃ I Cl Me Br Br F Br Me Br CH₃ I Cl Et Br Br F Br Et Br CH₃ I Cl i-Pr Br Br F Br i-Pr Br CH₃ I Cl t-Bu Br Br F Br t-Bu Br CH₃ I Br Me Cl Br Cl CF₃ Me Cl CH₃ I Br Et Cl Br Cl CF₃ Et Cl CH₃ I Br i-Pr Cl Br Cl CF₃ i-Pr Cl CH₃ I Br t-Bu Cl Br Cl CF₃ t-Bu Cl CH₃ I Br Me Br Br Cl CF₃ Me Br CH₃ I Br Et Br Br Cl CF₃ Et Br CH₃ I Br i-Pr Br Br Cl CF₃ i-Pr Br CH₃ I Br t-Bu Br Br Cl CF₃ t-Bu Br CH₃ CF₃ CF₃ Me Cl Br Cl Cl Me Cl CH₃ CF₃ CF₃ Et Cl Br Cl Cl Et Cl CH₃ CF₃ CF₃ i-Pr Cl Br Cl Cl i-Pr Cl CH₃ CF₃ CF₃ t-Bu Cl Br Cl Cl t-Bu Cl CH₃ CF₃ CF₃ Me Br Br Cl Cl Me Br CH₃ CF₃ CF₃ Et Br Br Cl Cl Et Br CH₃ CF₃ CF₃ i-Pr Br Br Cl Cl i-Pr Br CH₃ CF₃ CF₃ t-Bu Br Br Cl Cl t-Bu Br CH₃ CF₃ Cl Me Cl Br Cl Br Me Cl CH₃ CF₃ Cl Et Cl Br Cl Br Et Cl CH₃ CF₃ Cl i-Pr Cl Br Cl Br i-Pr Cl CH₃ CF₃ Cl t-Bu Cl Br Cl Br t-Bu Cl CH₃ CF₃ Cl Me Br Br Cl Br Me Br CH₃ CF₃ Cl Et Br Br Cl Br Et Br CH₃ CF₃ Cl i-Pr Br Br Cl Br i-Pr Br CH₃ CF₃ Cl t-Bu Br Br Cl Br t-Bu Br CH₃ CF₃ Br Me Cl Br Br CF₃ Me Cl CH₃ CF₃ Br Et Cl Br Br CF₃ Et Cl CH₃ CF₃ Br i-Pr Cl Br Br CF₃ i-Pr Cl CH₃ CF₃ Br t-Bu Cl Br Br CF₃ t-Bu Cl CH₃ CF₃ Br Me Br Br Br CF₃ Me Br CH₃ CF₃ Br Et Br Br Br CF₃ Et Br CH₃ CF₃ Br i-Pr Br Br Br CF₃ i-Pr Br CH₃ CF₃ Br t-Bu Br Br Br CF₃ t-Bu Br CH₃ Cl Cl n-Pr Cl Br Br Cl Me Cl CH₃ Cl Cl n-Bu Cl Br Br Cl Et Cl CH₃ Cl Cl s-Bu Cl Br Br Cl i-Pr Cl CH₃ Cl Cl i-Bu Cl Br Br Cl t-Bu Cl Cl F CF₃ Me Cl Br Br Cl Me Br Cl F CF₃ Et Cl Br Br Cl Et Br Cl F CF₃ i-Pr Cl Br Br Cl i-Pr Br Cl F CF₃ t-Bu Cl Br Br Cl t-Bu Br Cl F CF₃ Me Br Br Br Br Me Cl Cl F CF₃ Et Br Br Br Br Et Cl Cl F CF₃ i-Pr Br Br Br Br i-Pr Cl Cl F CF₃ t-Bu Br Br Br Br t-Bu Cl Cl F Cl Me Cl Br Br Br Me Br Cl F Cl Et Cl Br Br Br Et Br Cl F Cl i-Pr Cl Br Br Br i-Pr Br Cl F Cl t-Bu Cl Br Br Br t-Bu Br Cl F Cl Me Br Br I CF₃ Me Cl Cl F Cl Et Br Br I CF₃ Et Cl Cl F Cl i-Pr Br Br I CF₃ i-Pr Cl Cl F Cl t-Bu Br Br I CF₃ t-Bu Cl Cl F Br Me Cl Br I CF₃ Me Br Cl F Br Et Cl Br I CF₃ Et Br Cl F Br i-Pr Cl Br I CF₃ i-Pr Br Cl F Br t-Bu Cl Br I CF₃ t-Bu Br Cl F Br Me Br Br I Cl Me Cl Cl F Br Et Br Br I Cl Et Cl Cl F Br i-Pr Br Br I Cl i-Pr Cl Cl F Br t-Bu Br Br I Cl t-Bu Cl Cl Cl CF₃ Me Cl Br I Cl Me Br Cl Cl CF₃ Et Cl Br I Cl Et Br Cl Cl CF₃ i-Pr Cl Br I Cl i-Pr Br Cl Cl CF₃ t-Bu Cl Br I Cl t-Bu Br Cl Cl CF₃ Me Br Br I Br Me Cl Cl Cl CF₃ Et Br Br I Br Et Cl Cl Cl CF₃ i-Pr Br Br I Br i-Pr Cl Cl Cl CF₃ t-Bu Br Br I Br t-Bu Cl Cl Cl Cl Me Cl Br I Br Me Br Cl Cl Cl Et Cl Br I Br Et Br Cl Cl Cl i-Pr Cl Br I Br i-Pr Br Cl Cl Cl t-Bu Cl Br I Br t-Bu Br Cl Cl Cl Me Br Br CF₃ CF₃ Me Cl Cl Cl Cl Et Br Br CF₃ CF₃ Et Cl Cl Cl Cl i-Pr Br Br CF₃ CF₃ i-Pr Cl Cl Cl Cl t-Bu Br Br CF₃ CF₃ t-Bu Cl Cl Cl Br Me Cl Br CF₃ CF₃ Me Br Cl Cl Br Et Cl Br CF₃ CF₃ Et Br Cl Cl Br i-Pr Cl Br CF₃ CF₃ i-Pr Br Cl Cl Br t-Bu Cl Br CF₃ CF₃ t-Bu Br Cl Cl Br Me Br Br CF₃ Cl Me Cl Cl Cl Br Et Br Br CF₃ Cl Et Cl Cl Cl Br i-Pr Br Br CF₃ Cl i-Pr Cl Cl Cl Br t-Bu Br Br CF₃ Cl t-Bu Cl Cl Br CF₃ Me Cl Br CF₃ Cl Me Br Cl Br CF₃ Et Cl Br CF₃ Cl Et Br Cl Br CF₃ i-Pr Cl Br CF₃ Cl i-Pr Br Cl Br CF₃ t-Bu Cl Br CF₃ Cl t-Bu Br Cl Br CF₃ Me Br Br CF₃ Br Me Cl Cl Br CF₃ Et Br Br CF₃ Br Et Cl Cl Br CF₃ i-Pr Br Br CF₃ Br i-Pr Cl Cl Br CF₃ t-Bu Br Br CF₃ Br t-Bu Cl Cl Br Cl Me Cl Br CF₃ Br Me Br Cl Br Cl Et Cl Br CF₃ Br Et Br Cl Br Cl i-Pr Cl Br CF₃ Br i-Pr Br Cl Br Cl t-Bu Cl Br CF₃ Br t-Bu Br

TABLE 6

R⁴ R⁵ R⁶ R³ R⁹ R⁴ R⁵ R⁶ R³ R⁹ CH₃ F CF₃ Me Cl Cl Br Cl Me Br CH₃ F CF₃ Et Cl Cl Br Cl Et Br CH₃ F CF₃ i-Pr Cl Cl Br Cl i-Pr Br CH₃ F CF₃ t-Bu Cl Cl Br Cl t-Bu Br CH₃ F CF₃ Me Br Cl Br Br Me Cl CH₃ F CF₃ Et Br Cl Br Br Et Cl CH₃ F CF₃ i-Pr Br Cl Br Br i-Pr Cl CH₃ F CF₃ t-Bu Br Cl Br Br t-Bu Cl CH₃ F Cl Me Cl Cl Br Br Me Br CH₃ F Cl Et Cl Cl Br Br Et Br CH₃ F Cl i-Pr Cl Cl Br Br i-Pr Br CH₃ F Cl t-Bu Cl Cl Br Br t-Bu Br CH₃ F Cl Me Br Cl I CF₃ Me Cl CH₃ F Cl Et Br Cl I CF₃ Et Cl CH₃ F Cl i-Pr Br Cl I CF₃ i-Pr Cl CH₃ F Cl t-Bu Br Cl I CF₃ t-Bu Cl CH₃ F Br Me Cl Cl I CF₃ Me Br CH₃ F Br Et Cl Cl I CF₃ Et Br CH₃ F Br i-Pr Cl Cl I CF₃ i-Pr Br CH₃ F Br t-Bu Cl Cl I CF₃ t-Bu Br CH₃ F Br Me Br Cl I Cl Me Cl CH₃ F Br Et Br Cl I Cl Et Cl CH₃ F Br i-Pr Br Cl I Cl i-Pr Cl CH₃ F Br t-Bu Br Cl I Cl t-Bu Cl CH₃ Cl CF₃ Me Cl Cl I Cl Me Br CH₃ Cl CF₃ Et Cl Cl I Cl Et Br CH₃ Cl CF₃ i-Pr Cl Cl I Cl i-Pr Br CH₃ Cl CF₃ t-Bu Cl Cl I Cl t-Bu Br CH₃ Cl CF₃ Me Br Cl I Br Me Cl CH₃ Cl CF₃ Et Br Cl I Br Et Cl CH₃ Cl CF₃ i-Pr Br Cl I Br i-Pr Cl CH₃ Cl CF₃ t-Bu Br Cl I Br t-Bu Cl CH₃ Cl Cl Me Cl Cl I Br Me Br CH₃ Cl Cl Et Cl Cl I Br Et Br CH₃ Cl Cl i-Pr Cl Cl I Br i-Pr Br CH₃ Cl Cl t-Bu Cl Cl I Br t-Bu Br CH₃ Cl Cl Me Br Cl CF₃ CF₃ Me Cl CH₃ Cl Cl Et Br Cl CF₃ CF₃ Et Cl CH₃ Cl Cl i-Pr Br Cl CF₃ CF₃ i-Pr Cl CH₃ Cl Cl t-Bu Br Cl CF₃ CF₃ t-Bu Cl CH₃ Cl Br Me Cl Cl CF₃ CF₃ Me Br CH₃ Cl Br Et Cl Cl CF₃ CF₃ Et Br CH₃ Cl Br i-Pr Cl Cl CF₃ CF₃ i-Pr Br CH₃ Cl Br t-Bu Cl Cl CF₃ CF₃ t-Bu Br CH₃ Cl Br Me Br Cl CF₃ Cl Me Cl CH₃ Cl Br Et Br Cl CF₃ Cl Et Cl CH₃ Cl Br i-Pr Br Cl CF₃ Cl i-Pr Cl CH₃ Cl Br t-Bu Br Cl CF₃ Cl t-Bu Cl CH₃ Br CF₃ Me Cl Cl CF₃ Cl Me Br CH₃ Br CF₃ Et Cl Cl CF₃ Cl Et Br CH₃ Br CF₃ i-Pr Cl Cl CF₃ Cl i-Pr Br CH₃ Br CF₃ i-Bu Cl Cl CF₃ Cl t-Bu Br CH₃ Br CF₃ Me Br Cl CF₃ Br Me Cl CH₃ Br CF₃ Et Br Cl CF₃ Br Et Cl CH₃ Br CF₃ i-Pr Br Cl CF₃ Br i-Pr Cl CH₃ Br CF₃ t-Bu Br Cl CF₃ Br t-Bu Cl CH₃ Br Cl Me Cl Cl CF₃ Br Me Br CH₃ Br Cl Et Cl Cl CF₃ Br Et Br CH₃ Br Cl i-Pr Cl Cl CF₃ Br i-Pr Br CH₃ Br Cl t-Bu Cl Cl CF₃ Br t-Bu Br CH₃ Br Cl Me Br Cl Cl Cl n-Pr Cl CH₃ Br Cl Et Br Cl Cl Cl n-Bu Cl CH₃ Br Cl i-Pr Br Cl Cl Cl s-Bu Cl CH₃ Br Cl t-Bu Br Cl Cl Cl i-Bu Cl CH₃ Br Br Me Cl Br F CF₃ Me Cl CH₃ Br Br Et Cl Br F CF₃ Et Cl CH₃ Br Br i-Pr Cl Br F CF₃ i-Pr Cl CH₃ Br Br t-Bu Cl Br F CF₃ t-Bu Cl CH₃ Br Br Me Br Br F CF₃ Me Br CH₃ Br Br Et Br Br F CF₃ Et Br CH₃ Br Br i-Pr Br Br F CF₃ i-Pr Br CH₃ Br Br t-Bu Br Br F CF₃ t-Bu Br CH₃ I CF₃ Me Cl Br F Cl Me Cl CH₃ I CF₃ Et Cl Br F Cl Et Cl CH₃ I CF₃ i-Pr Cl Br F Cl i-Pr Cl CH₃ I CF₃ t-Bu Cl Br F Cl t-Bu Cl CH₃ I CF₃ Me Br Br F Cl Me Br CH₃ I CF₃ Et Br Br F Cl Et Br CH₃ I CF₃ i-Pr Br Br F Cl i-Pr Br CH₃ I CF₃ t-Bu Br Br F Cl t-Bu Br CH₃ I Cl Me Cl Br F Br Me Cl CH₃ I Cl Et Cl Br F Br Et Cl CH₃ I Cl i-Pr Cl Br F Br i-Pr Cl CH₃ I Cl t-Bu Cl Br F Br t-Bu Cl CH₃ I Cl Me Br Br F Br Me Br CH₃ I Cl Et Br Br F Br Et Br CH₃ I Cl i-Pr Br Br F Br i-Pr Br CH₃ I Cl t-Bu Br Br F Br t-Bu Br CH₃ I Br Me Cl Br Cl CF₃ Me Cl CH₃ I Br Et Cl Br Cl CF₃ Et Cl CH₃ I Br i-Pr Cl Br Cl CF₃ i-Pr Cl CH₃ I Br t-Bu Cl Br Cl CF₃ t-Bu Cl CH₃ I Br Me Br Br Cl CF₃ Me Br CH₃ I Br Et Br Br Cl CF₃ Et Br CH₃ I Br i-Pr Br Br Cl CF₃ i-Pr Br CH₃ I Br t-Bu Br Br Cl CF₃ t-Bu Br CH₃ CF₃ CF₃ Me Cl Br Cl Cl Me Cl CH₃ CF₃ CF₃ Et Cl Br Cl Cl Et Cl CH₃ CF₃ CF₃ i-Pr Cl Br Cl Cl i-Pr Cl CH₃ CF₃ CF₃ t-Bu Cl Br Cl Cl t-Bu Cl CH₃ CF₃ CF₃ Me Br Br Cl Cl Me Br CH₃ CF₃ CF₃ Et Br Br Cl Cl Et Br CH₃ CF₃ CF₃ i-Pr Br Br Cl Cl i-Pr Br CH₃ CF₃ CF₃ t-Bu Br Br Cl Cl t-Bu Br CH₃ CF₃ Cl Me Cl Br Cl Br Me Cl CH₃ CF₃ Cl Et Cl Br Cl Br Et Cl CH₃ CF₃ Cl i-Pr Cl Br Cl Br i-Pr Cl CH₃ CF₃ Cl t-Bu Cl Br Cl Br t-Bu Cl CH₃ CF₃ Cl Me Br Br Cl Br Me Br CH₃ CF₃ Cl Et Br Br Cl Br Et Br CH₃ CF₃ Cl i-Pr Br Br Cl Br i-Pr Br CH₃ CF₃ Cl t-Bu Br Br Cl Br t-Bu Br CH₃ CF₃ Br Me Cl Br Br CF₃ Me Cl CH₃ CF₃ Br Et Cl Br Br CF₃ Et Cl CH₃ CF₃ Br i-Pr Cl Br Br CF₃ i-Pr Cl CH₃ CF₃ Br t-Bu Cl Br Br CF₃ t-Bu Cl CH₃ CF₃ Br Me Br Br Br CF₃ Me Br CH₃ CF₃ Br Et Br Br Br CF₃ Et Br CH₃ CF₃ Br i-Pr Br Br Br CF₃ i-Pr Br CH₃ CF₃ Br t-Bu Br Br Br CF₃ t-Bu Br CH₃ Cl Cl n-Pr Cl Br Br Cl Me Cl CH₃ Cl Cl n-Bu Cl Br Br Cl Et Cl CH₃ Cl Cl s-Bu Cl Br Br Cl i-Pr Cl CH₃ Cl Cl i-Bu Cl Br Br Cl t-Bu Cl Cl F CF₃ Me Cl Br Br Cl Me Br Cl F CF₃ Et Cl Br Br Cl Et Br Cl F CF₃ i-Pr Cl Br Br Cl i-Pr Br Cl F CF₃ t-Bu Cl Br Br Cl t-Bu Br Cl F CF₃ Me Br Br Br Br Me Cl Cl F CF₃ Et Br Br Br Br Et Cl Cl F CF₃ i-Pr Br Br Br Br i-Pr Cl Cl F CF₃ t-Bu Br Br Br Br t-Bu Cl Cl F Cl Me Cl Br Br Br Me Br Cl F Cl Et Cl Br Br Br Et Br Cl F Cl i-Pr Cl Br Br Br i-Pr Br Cl F Cl t-Bu Cl Br Br Br t-Bu Br Cl F Cl Me Br Br I CF₃ Me Cl Cl F Cl Et Br Br I CF₃ Et Cl Cl F Cl i-Pr Br Br I CF₃ i-Pr Cl Cl F Cl t-Bu Br Br I CF₃ t-Br Cl Cl F Br Me Cl Br I CF₃ Me Br Cl F Br Et Cl Br I CF₃ Et Br Cl F Br i-Pr Cl Br I CF₃ i-Pr Br Cl F Br t-Bu Cl Br I CF₃ t-Bu Br Cl F Br Me Br Br I Cl Me Cl Cl F Br Et Br Br I Cl Et Cl Cl F Br i-Pr Br Br I Cl i-Pr Cl Cl F Br t-Bu Br Br I Cl t-Bu Cl Cl Cl CF₃ Me Cl Br I Cl Me Br Cl Cl CF₃ Et Cl Br I Cl Et Br Cl Cl CF₃ i-Pr Cl Br I Cl i-Pr Br Cl Cl CF₃ t-Bu Cl Br I Cl t-Bu Br Cl Cl CF₃ Me Br Br I Br Me Cl Cl Cl CF₃ Et Br Br I Br Et Cl Cl Cl CF₃ i-Pr Br Br I Br i-Pr Cl Cl Cl CF₃ t-Bu Br Br I Br t-Bu Cl Cl Cl Cl Me Cl Br I Br Me Br Cl Cl Cl Et Cl Br I Br Et Br Cl Cl Cl i-Pr Cl Br I Br i-Pr Br Cl Cl Cl t-Bu Cl Br I Br t-Bu Br Cl Cl Cl Me Br Br CF₃ CF₃ Me Cl Cl Cl Cl Et Br Br CF₃ CF₃ Et Cl Cl Cl Cl i-Pr Br Br CF₃ CF₃ i-Pr Cl Cl Cl Cl t-Bu Br Br CF₃ CF₃ t-Bu Cl Cl Cl Br Me Cl Br CF₃ CF₃ Me Br Cl Cl Br Et Cl Br CF₃ CF₃ Et Br Cl Cl Br i-Pr Cl Br CF₃ CF₃ i-Pr Br Cl Cl Br t-Bu Cl Br CF₃ CF₃ t-Bu Br Cl Cl Br Me Br Br CF₃ Cl Me Cl Cl Cl Br Et Br Br CF₃ Cl Et Cl Cl Cl Br i-Pr Br Br CF₃ Cl i-Pr Cl Cl Cl Br t-Bu Br Br CF₃ Cl t-Bu Cl Cl Br CF₃ Me Cl Br CF₃ Cl Me Br Cl Br CF₃ Et Cl Br CF₃ Cl Et Br Cl Br CF₃ i-Pr Cl Br CF₃ Cl i-Pr Br Cl Br CF₃ t-Bu Cl Br CF₃ Cl t-Bu Br Cl Br CF₃ Me Br Br CF₃ Br Me Cl Cl Br CF₃ Et Br Br CF₃ Br Et Cl Cl Br CF₃ i-Pr Br Br CF₃ Br i-Pr Cl Cl Br CF₃ t-Bu Br Br CF₃ Br t-Bu Cl Cl Br Cl Me Cl Br CF₃ Br Me Br Cl Br Cl Et Cl Br CF₃ Br Et Br Cl Br Cl i-Pr Cl Br CF₃ Br i-Pr Br Cl Br Cl t-Bu Cl Br CF₃ Br t-Bu Br

As shown in Scheme 7 and further illustrated in Examples 4 and 5, the benzoxazines of Formula 10a-b such as those listed in Tables 7 and 8 are useful for preparing the compounds of Formula I, including those listed in Tables 2 and 5.

TABLE 7 10a

W X Y Z R⁴ R⁶ R⁹ CH CH CH CH Me CF₃ Me CH CH CH CH Cl CF₃ Me CH CH CH CH Br CF₃ Me CH CH CH CH Me Cl Me CH CH CH CH Cl Cl Me CH CH CH CH Br Cl Me CH CH CH CH Me Br Me CH CH CH CH Cl Br Me CH CH CH CH Br Br Me CH CH CH CH Me CN Me CH CH CH CH Cl CN Me CH CH CH CH Br CN Me CH CH CH CH Me CF₃ F CH CH CH CH Cl CF₃ F CH CH CH CH Br CF₃ F CH CH CH CH Me Cl F CH CH CH CH Cl Cl F CH CH CH CH Br Cl F CH CH CH CH Me Br F CH CH CH CH Cl Br F CH CH CH CH Br Br F CH CH CH CH Me CN F CH CH CH CH Cl CN F CH CH CH CH Br CN F CH CH CH CH Me CF₃ Cl CH CH CH CH Cl CF₃ Cl CH CH CH CH Br CF₃ Cl CH CH CH CH Me Cl Cl CH CH CH CH Cl Cl Cl CH CH CH CH Br Cl Cl CH CH CH CH Me Br Cl CH CH CH CH Cl Br Cl CH CH CH CH Br Br Cl CH CH CH CH Me CN Cl CH CH CH CH Cl CN Cl CH CH CH CH Br CN Cl CH CH CH CH Me CF₃ Br CH CH CH CH Cl CF₃ Br CH CH CH CH Br CF₃ Br CH CH CH CH Me Cl Br CH CH CH CH Cl Cl Br CH CH CH CH Br Cl Br CH CH CH CH Me Br Br CH CH CH CH Cl Br Br CH CH CH CH Br Br Br CH CH CH CH Me CN Br CH CH CH CH Cl CN Br CH CH CH CH Br CN Br CH CH CH CH Me CF₃ CN CH CH CH CH Cl CF₃ CN CH CH CH CH Br CF₃ CN CH CH CH CH Me Cl CN CH CH CH CH Cl Cl CN CH CH CH CH Br Cl CN CH CH CH CH Me Br CN CH CH CH CH Cl Br CN CH CH CH CH Br Br CN CH CH CH CH Me CN CN CH CH CH CH Cl CN CN CH CH CH CH Br CN CN CH CH CH N Me CF₃ Me CH CH CH N Cl CF₃ Me CH CH CH N Br CF₃ Me CH CH CH N Me Cl Me CH CH CH N Cl Cl Me CH CH CH N Br Cl Me CH CH CH N Me Br Me CH CH CH N Cl Br Me CH CH CH N Br Br Me CH CH CH N Me CN Me CH CH CH N Cl CN Me CH CH CH N Br CN Me CH CH CH N Me CF₃ F CH CH CH N Cl CF₃ F CH CH CH N Br CF₃ F CH CH CH N Me Cl F CH CH CH N Cl Cl F CH CH CH N Br Cl F CH CH CH N Me Br F CH CH CH N Cl Br F CH CH CH N Br Br F CH CH CH N Me CN F CH CH CH N Cl CN F CH CH CH N Br CN F CH CH CH N Me CF₃ Cl CH CH CH N Cl CF₃ Cl CH CH CH N Br CF₃ Cl CH CH CH N Me Cl Cl CH CH CH N Cl Cl Cl CH CH CH N Br Cl Cl CH CH CH N Me Br Cl CH CH CH N Cl Br Cl CH CH CH N Br Br Cl CH CH CH N Me CN Cl CH CH CH N Cl CN Cl CH CH CH N Br CN Cl CH CH CH N Me CF₃ Br CH CH CH N Cl CF₃ Br CH CH CH N Br CF₃ Br CH CH CH N Me Cl Br CH CH CH N Cl Cl Br CH CH CH N Br Cl Br CH CH CH N Me Br Br CH CH CH N Cl Br Br CH CH CH N Br Br Br CH CH CH N Me CN Br CH CH CH N Cl CN Br CH CH CH N Br CN Br CH CH CH N Me CF₃ CN CH CH CH N Cl CF₃ CN CH CH CH N Br CF₃ CN CH CH CH N Me Cl CN CH CH CH N Cl Cl CN CH CH CH N Br Cl CN CH CH CH N Me Br CN CH CH CH N Cl Br CN CH CH CH N Br Br CN CH CH CH N Me CN CN CH CH CH N Cl CN CN CH CH CH N Br CN CN C—Cl CH CH CH Me CF₃ Cl C—F CH CH CH Me CF₃ F CH CH CH CH Me CF₃ ethynyl CH CH CH CH Me CF₃ I CH CH CH CH Me CF₃ SO₂Me C—Cl CH CH CH Cl CF₃ Cl C—F CH CH CH Cl CF₃ F CH CH CH CH Cl CF₃ ethynyl CH CH CH CH Cl CF₃ I CH CH CH CH Cl CF₃ SO₂Me C—Cl CH CH CH Me Br Cl C—F CH CH CH Me Br F CH CH CH CH Me Br ethynyl CH CH CH CH Me Br I CH CH CH CH Me Br SO₂Me C—Cl CH CH CH Cl Br Cl C—F CH CH CH Cl Br F CH CH CH CH Cl Br ethynyl CH CH CH CH Cl Br I CH CH CH CH Cl Br SO₂Me C—Cl CH CH N Me CF₃ Cl C—F CH CH N Me CF₃ F CH CH CH N Me CF₃ ethynyl CH CH CH N Me CF₃ I CH CH CH N Me CF₃ SO₂Me C—Cl CH CH N Cl CF₃ Cl C—F CH CH N Cl CF₃ F CH CH CH N Cl CF₃ ethynyl CH CH CH N Cl CF₃ I CH CH CH N Cl CF₃ SO₂Me C—Cl CH CH N Me Br Cl C—F CH CH N Me Br F CH CH CH N Me Br ethynyl CH CH CH N Me Br I CH CH CH N Me Br SO₂Me C—Cl CH CH N Cl Br Cl C—F CH CH N Cl Br F CH CH CH N Cl Br ethynyl CH CH CH N Cl Br I CH CH CH N Cl Br SO₂Me CH N CH N Me CF₃ H CH N CH N Me CF₃ Me CH N CH N Me CF₃ Cl CH N CH N Cl CF₃ H CH N CH N Cl CF₃ Me CH N CH N Cl CF₃ Cl CH N CH N Me CN H CH N CH N Me CN Me CH N CH N Me CN Cl CH N CH N Cl CN H CH N CH N Cl CN Me CH N CH N Cl CN Cl CH N CH N Me Br H CH N CH N Me Br Me CH N CH N Me Br Cl CH N CH N Cl Br H CH N CH N Cl Br Me CH N CH N Cl Br Cl CH CH N N Me CF₃ H CH CH N N Me CF₃ Me CH CH N N Me CF₃ Cl CH CH N N Cl CF₃ H CH CH N N Cl CF₃ Me CH CH N N Cl CF₃ Cl CH CH N N Me CN H CH CH N N Me CN Me CH CH N N Me CN Cl CH CH N N Cl CN H CH CH N N Cl CN Me CH CH N N Cl CN Cl CH CH N N Me Br H CH CH N N Me Br Me CH CH N N Me Br Cl CH CH N N Cl Br H CH CH N N Cl Br Me CH CH N N Cl Br Cl CH CH N N Me CF₃ H CH CH N N Me CF₃ Me CH CH N N Me CF₃ Cl CH CH N N Cl CF₃ H CH CH N N Cl CF₃ Me CH CH N N Cl CF₃ Cl CH CH N N Me CN H CH CH N N Me CN Me CH CH N N Mc CN Cl CH CH N N Cl CN H CH CH N N Cl CN Me CH CH N N Cl CN Cl CH CH N N Me Br H CH CH N N Me Br Me CH CH N N Me Br Cl CH CH N N Cl Br H CH CH N N Cl Br Me CH CH N N Cl Br Cl

TABLE 8 10b

R⁴ R⁵ R⁶ R⁹ R⁴ R⁵ R⁶ R⁹ CH₃ F CF₃ Cl Cl Br Cl Br CH₃ F CF₃ Br Cl Br Br Cl CH₃ F Cl Cl Cl Br Br Br CH₃ F Cl Br Cl I CF₃ Cl CH₃ F Br Cl Cl I CF₃ Br CH₃ F Br Br Cl I Cl Cl CH₃ Cl CF₃ Cl Cl I Cl Br CH₃ Cl CF₃ Br Cl I Br Cl CH₃ Cl Cl Cl Cl I Br Br CH₃ Cl Cl Br Cl CF₃ CF₃ Cl CH₃ Cl Br Cl Cl CF₃ CF₃ Br CH₃ Cl Br Br Cl CF₃ Cl Cl CH₃ Br CF₃ Cl Cl CF₃ Cl Br CH₃ Br CF₃ Br Cl CF₃ Br Cl CH₃ Br Cl Cl Cl CF₃ Br Br CH₃ Br Cl Br Cl Cl Cl Cl CH₃ Br Br Cl Br F CF₃ Cl CH₃ Br Br Br Br F CF₃ Br CH₃ I CF₃ Cl Br F Cl Cl CH₃ I CF₃ Br Br F Cl Br CH₃ I Cl Cl Br F Br Cl CH₃ I Cl Br Br F Br Br CH₃ I Br Cl Br Cl CF₃ Cl CH₃ I Br Br Br Cl CF₃ Br CH₃ CF₃ CF₃ Cl Br Cl Cl Cl CH₃ CF₃ CF₃ Br Br Cl Cl Br CH₃ CF₃ Cl Cl Br Cl Br Cl CH₃ CF₃ Cl Br Br Cl Br Br CH₃ CF₃ Br Cl Br Br CF₃ Cl CH₃ CF₃ Br Br Br Br CF₃ Br CH₃ Cl Cl Cl Br Br Cl Cl Cl F CF₃ Cl Br Br Cl Br Cl F CF₃ Br Br Br Br Cl Cl F Cl Cl Br Br Br Br Cl F Cl Br Br I CF₃ Cl Cl F Br Cl Br I CF₃ Br Cl F Br Br Br I Cl Cl Cl Cl CF₃ Cl Br I Cl Br Cl Cl CF₃ Br Br I Br Cl Cl Cl Cl Cl Br I Br Br Cl Cl Cl Br Br CF₃ CF₃ Cl Cl Cl Br Cl Br CF₃ CF₃ Br Cl Cl Br Br Br CF₃ Cl Cl Cl Br CF₃ Cl Br CF₃ Cl Br Cl Br CF₃ Br Br CF₃ Br Cl Cl Br Cl Cl Br CF₃ Br Br

Formulation/Utility

Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible (“wettable”) or water-soluble. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient. Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation.

The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges that add up to 100 percent by weight.

Weight Percent Active Ingredient Diluent Surfactant Water-Dispersible and 5-90  0-94 1-15 Water-soluble Granules, Tablets and Powders. Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (including Emulsifiable Concentrates) Dusts 1-25 70-99 0-5  Granules and Pellets 0.01-99      5-99.99 0-15 High Strength Compositions 90-99   0-10 0-2 

Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.

Surfactants include, for example, polyethoxylated alcohols, polyethoxylated allylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthRlenes, oils of olive, castor, linseed, twig, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahycirofurfuryl alcohol.

Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. Pat. No. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration”, Chemical Engineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and PCT Publication WO 91/13546. Pellets can be prepared as described in U.S. Pat. No. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. Pat. No. 4,144,050, U.S. Pat. No. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. Pat. No. 5,180,587, U.S. Pat. No. 5,232,701 and U.S. Pat. No. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. Pat. No. 3,299,566.

For further information regarding the art of formulation, see T. S. Woods, “The Formulator's Toolbox—Product Forms for Modern Agriculture” in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also U.S. Pat. No. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Kingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.

In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Table A.

Example A

Wettable Powder Compound 214 65.0%  dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%. 

Example B

Granule Compound 214 10.0% attapulgite granules (low volatile matter,  90.0%. 0.71/0.30 mm; U.S.S. No. 25-50 sieves)

Example C

Extruded Pellet Compound 214 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate  5.0% sodium alkylnaphthalenesulfonate  1.0% calcium/magnesium bentonite  59.0%.

Example D

Emulsifiable Concentrate Compound 214 20.0% blend of oil soluble sulfonates 10.0% and polyoxyethylene ethers isophorone  70.0%.

Example E

Granule Compound 214 0.5% cellulose 2.5% lactose 4.0% cornmeal 93.0%. 

Compounds of this invention are characterized by favorable metabolic and/or soil residual patterns and exhibit activity controlling a spectrum of agronomic and non-agronomic invertebrate pests. (In the context of this disclosure “invertebrate pest control” means inhibition of invertebrate pest development (including mortality) that causes significant reduction in feeding or other injury or damage caused by the pest; related expressions are defined analogously.) As referred to in this disclosure, the term “invertebrate pest” includes arthropods, gastropods and nematodes of economic importance as pests. The term “arthropod” includes insects, mites, spiders, scorpions, centipedes, millipedes, pill bugs and symphylans. The term “gastropod” includes snails, slugs and other Stylommatophora. The term “nematode” includes all of the helminths, such as: roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes (Tematoda), Acanthocephala, and tapeworms (Cestoda). Those skilled in the art will recognize that not all compounds are equally effective against all pests. Compounds of this invention display activity against economically important agronomic, forest, greenhouse, nursery, ornamentals, food and fiber, public and animal health, domestic and commercial structure, household, and stored product pests. These include larvae of the order Lepidoptera, such as armyworms, cutworms, loopers, and heliothines in the family Noctuidae (e.g., fall armyworm (Spodoptera fugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hübner), black cutworm (Agrotis ipsilon Hufnagel), cabbage looper (Trichoplusia ni Hübner), tobacco budworm (Heliothis virescens Fabricius)); borers, casebearers, webworms, coneworms, cabbageworrns and skeletonizers from the family Pyralidae (e.g., European corn borer (Ostrinia nubilalis Hübner), navel orangeworm (Amyelois transitella Walker), corn root webworm (Crambus caliginosellus Clemens), sod webworm (Herpetogramma licarsisalis Walker)); leafrollers, budworms, seed worms, and fruit worms in the family Tortricidae (e.g., codling moth (Cydia pomonella Linnaeus), grape berry moth (Endopiza viteana Clemens), oriental fruit moth (Grapholita molesta Busck)); and many other economically important lepidoptera(e.g., diamondback moth (Plutella xylostella Linnaeus), pink bollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantria dispar Linnaeus)); nymphs and adults of the order Blattodea including cockroaches from the families Blattellidae and Blattidae (e.g., oriental cockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatella asahinai Mizukubo), German cockroach (Blattella germanica Linnaeus), brownbanded cockroach (Supella longipalpa Fabricius), American cockroach (Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunnea Burmeister), Madeira cockroach (Leucophaea maderae Fabricius)); foliar feeding larvae and adults of the order Coleoptera including weevils from the families Anthribidae, Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptrus omophilus Kuschel), granary weevil (Sitophilus granarius Linnaeus), rice weevil (Sitophilus olyzae Linnaeus)); flea beetles, cucumber beetles, rootworms, leaf beetles, potato beetles, and leafminers in the family Chrysomelidae (e.g., Colorado potato beetle (Leptinotarsa decemlineata Say), western corn rootwonn (Diabrotica virgifera virgifera LeConte)); chafers and other beetles from the family Scaribaeidae (e.g., Japanese beetle (Popillia japonica Newman) and European chafer (Rhizotrogus majalis Razoumowsky)); carpet beetles from the family Dermestidae; wireworms from the family Elateridae; bark beetles from the family Scolytidae and flour beetles from the family Tenebrionidae. In addition it includes: adults and larvae of the order Dermaptera including earwigs from the family Forficulidae (e.g., European earwig (Fotficula auricularia Linnaeus), black earwig (Chelisoches morio Fabricius)); adults and nymphs of the orders Hemiptera and Homoptera such as, plant bugs from the family Miridae, cicadas from the family Cicadidae, leafhoppers (e.g. Empoasca spp.) from the family Cicadellidae, planthoppers from the families Fulgoroidae and Delphacidae, treehoppers from the family Membracidae, psyllids from the family Psyllidae, whiteflies from the family Aleyrodidae, aphids from the family Aphididae, phylloxera from the family Phylloxeridae, mealybugs from the family Pseudococcidae, scales from the families Coccidae, Diaspididae and Margarodidae, lace bugs from the family Tingidae, stink bugs from the family Pentatomidae, cinch bugs (e.g., Blissus spp.) and other seed bugs from the family Lygaeidae, spittlebugs from the family Cercopidae squash bugs from the family Coreidae, and red bugs and cotton stainers from the family Pyrrhocoridae. Also included are adults and larvae of the order Acari (mites) such as spider mites and red mites in the family Tetranychidae (e.g., European red mite (Panonychus ulmi Koch), two spotted spider mite (Tetranychus urticae Koch), McDaniel mite (Tetranychus mcdanieli McGregor)), flat mites in the family Tenuipalpidae (e.g., citrus flat mite (Brevipalpus lewlsi McGregor)), rust and bud mites in the family Eriophyidae and other foliar feeding mites and mites important in human and animal health, i.e. dust mites in the family Epidermoptidae, follicle mites in the family Demodicidae, grain mites in the family Glycyphagidae, ticks in the order Ixodidae (e.g., deer tick (Ixodes scapularis Say), Australian paralysis tick (Ixodes holocyclus Neumann), American dog tick (Dermacentor variabilis Say), lone star tick (Amblyomma americanum Linnaeus) and scab and itch mites in the families Psoroptidae, Pyemotidae, and Sarcoptidae; adults and immatures of the order Orthoptera including grasshoppers, locusts and crickets (e.g., migratory grasshoppers (e.g., Melanoplus sanguinipes Fabricius, M. differentialis Thomas), American grasshoppers (e.g., Schistocerca americana Drury), desert locust (Schistocerca gregaria Forskal), migratory locust (Locusta migratoria Linnaeus), house cricket (Acheta domesticus Linnaeus), mole crickets (Gryllotalpa spp.)); adults and immatures of the order Diptera including leafminers, midges, fruit flies (Tephritidae), frit flies (e.g., Oscinella frit Linnaeus), soil maggots, house flies (e.g., Musca domestica Linnaeus), lesser house flies (e.g., Fannia canicularis Linnaeus, F. femoralis Stein), stable flies (e.g., Stomoxys calcitrans Linnaeus), face flies, horn flies, blow flies (e.g., Cluysomya spp., Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanus spp.), bot flies (e.g., Gastrophilus spp., Oestrus spp.), cattle grubs (e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g., Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g., Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimulium spp., Simulium spp.), biting midges, sand flies, sciarids, and other Nematocera; adults and immatures of the order Thysanoptera including onion thrips (Thrips tabaci Lindeman) and other foliar feeding thrips; insect pests of the order Hymenoptera including ants (e.g., red carpenter ant (Camponotus ferrugineus Fabricius), black carpenter ant (Camponotus pennsylvanicus De Geer), Pharaoh ant (Monomorium pharaonis Linnaeus), little fire ant (Wasmannia auropunctata Roger), fire ant (Solenopsis geminata Fabricius), red imported fire ant (Solenopsis invicta Buren), Argentine ant (Iridomynnex humilis Mayr), crazy ant (Paratrechina longicornis Latreille), pavement ant (Tetrarnorium caespitum Linnaeus), cornfield ant (Lasius alienus Förster), odorous house ant (Tapinoma sessile Say)), bees (including carpenter bees), hornets, yellow jackets and wasps; insect pests of the order Isoptera including the eastern subterranean termite (Reticulitermes flavipes Kollar), western subterranean termite (Reticulitermes hesperus Banks), Formosan subterranean termite (Coptotermes formosanus Shiraki), West Indian drywood termite (Incisitermes immigrans Snyder) and other termites of economic importance; insect pests of the order Thysanura such as silverfish (Lepisma saccharina Linnaeus) and firebrat (Thermobia domestica Packard); insect pests of the order Mallophaga and including the head louse (Pediculus humanus capitis De Geer), body louse (Pediculus humanus humanus Linnaeus), chicken body louse (Menacanthus stramineus Nitszch), dog biting louse (Trichodectes canis De Geer), fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicola ovis Schrank), short-nosed cattle louse (Haematopinus eurysternus Nitzsch), long-nosed cattle louse (Linognathus vitull Linnaeus) and other sucking and chewing parasitic lice that attack man and animals; insect pests of the order Siphonoptera including the oriental rat flea (Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felis Bouche), dog flea (Ctenocephalides canis Curtis), hen flea (Ceratophyllus gallinae Schrank), sticktight flea (Echidnophaga gallinacea Westwood), human flea (Pulex irritans Linnaeus) and other fleas afflicting mammals and birds. Additional arthropod pests covered include: spiders in the order Araneae such as the brown recluse spider (Loxosceles reclusa Gertsch & Mulaik) and the black widow spider (Latrodectus mactans Fabricius), and centipedes in the order Scutigeromorpha such as the house centipede (Scutigera coleoptrata Linnaeus). Activity also includes members of the Classes Nematoda, Cestoda, Trematoda, and Acanthocephala including economically important members of the orders Strongylida, Ascaridida, Oxyurida, Rhabditida, Spirurida, and Enoplida such as but not limited to economically important agricultural pests (i.e. root knot nematodes in the genus Meloidogyne, lesion nematodes in the genus Pratylenchus, stubby root nematodes in the genus Trichodorus, etc.) and animal and human health pests (i.e. all economically important flukes, tapeworms, and roundworms, such as Strongylus vulgaris in horses, Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilaria immitis Leidy in dogs, Anoplocephala perfoliata in horses, Fasciola hepatica Linnaeus in ruminants, etc.).

Compounds of the invention show particularly high activity against pests in the order Lepidoptera (e.g., Alabama argillacea Hübner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm), Earias vittella Fabricius (spotted bollworm), Helicoverpa armigera Hübner (American bollworm), Helicoverpa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm), Hezpetogramma licamisalis Walker (sod webworm), Lobesia botrana Denis & Schiffermüller (grape berry moth), Pectinophora gossypiella Saunders (pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer), Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diamondback moth), Spodoptera exigua Hübner (beet armyworm), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperda J. E. Smith (fall armyworm), Trichoplusia ni Hübner (cabbage looper) and Tuta absoluta Meyrick (tomato leafminer)). Compounds of the invention also have commercially significant activity on members from the order Homoptera including: Acyrthisiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaeblii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy (mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophium dirrhodum Walker (cereal aphid), Macrosipum euphorbiae Thomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (corn leaf aphid), Rhopalosiphum padi Linnaeus (bird cherry-oat aphid), Schizaphis graminum Rondani (greenbug), Sitobion avenae Fabricius (English grain aphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid), and Toxoptera citricida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix Pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes citri Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhouse whitefly); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stål (rice leafhopper), Nilaparvata lugens Still (brown planthopper), Peregrinus maidis Ashmead (corn planthopper), Sogatella furcifera Horvath (white-backed planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocyba pomaria McAtee white apple leafhopper, Thythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotus perniciosus Comstock (San Jose scale); Planococcus citri Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmon psylla). These compounds also have activity on members from the order Hemiptera including: Acrosternum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-Schäffer (cotton stainer), Euchistus serous Say (brown stink bug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug), Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezara viridula Linnaeus (southern green stink bug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cotton fleahopper). Other insect orders controlled by compounds of the invention include Thysanoptera (e.g., Frankliniella occidentalis Pergande (western flower thrip), Scirthothrips citri Moulton (citrus thrip), Sericothrips variabilis Beach (soybean thrip), and Thrips tabaci Lindeman (onion thrip); and the order Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius).

Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators such as, rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, other biologically active compounds or entonropathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural utility. Thus compositions of the present invention can further comprise a biologically effective amount of at least one additional biologically active compound or agent. Examples of such biologically active compounds or agents with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin, zinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromnine, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon and triflumuron; fungicides such as acibenzolar, azoxystrobin, benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate), bromuconazole, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, (S)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide (RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole, (S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one (RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil, flumetover (RPA 403397), flumorf/flumorlin (SYP-L190), fluoxastrobin (HEC 5725), fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658), hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin (SSF-126), metrafenone (AC 375839), myclobutanil, neo-asozin (ferric methanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU 6476), pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon, tiadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin and vinclozolin; nematocides such as aldicarb, oxamyl and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis including ssp. aizawai and kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.

A general reference for these agricultural protectants is The Pesticide Manual, 12th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2000.

Preferred insecticides and acaricides for mixing with compounds of this invention include pyrethroids such as cypermethrin, cyhalothrin, cyfluthrin and beta-cyfluthrin, esfenvalerate, fenvalerate and tralomethrin; carbamates such as fenothicarb, methomyl, oxamyl and thiodicarb; neonicotinoids such as clothianidin, imidacloprid and thiacloprid, neuronal sodium channel blockers such as indoxacarb, insecticidal macrocyclic lactones such as spinosad, abamectin, avermectin and emamectin; γ-aminobutyric acid (GABA) antagonists such as endosulfan, ethiprole and fipronil; insecticidal ureas such as flufenoxuron and triflumuron, juvenile hormone mimics such as diofenolan and pyriproxyfen; pymetrozine; and amitraz. Preferred biological agents for mixing with compounds of this invention include Bacillus thuringiensis and Bacillus thuringiensis delta endotoxin as well as naturally occurring and genetically modified viral insecticides including members of the family Baculoviridae as well as entomophagous fungi.

Most preferred mixtures include a mixture of a compound of this invention with cyhalothrin; a mixture of a compound of this invention with beta-cyfluthrin; a mixture of a compound of this invention with esfenvalerate; a mixture of a compound of this invention with methomyl; a mixture of a compound of this invention with imidacloprid; a mixture of a compound of this invention with thiacloprid; a mixture of a compound of this invention with indoxacarb; a mixture of a compound of this invention with abamectin; a mixture of a compound of this invention with endosulfan; a mixture of a compound of this invention with ethiprole; a mixture of a compound of this invention with fipronil; a mixture of a compound of this invention with flufenoxuron; a mixture of a compound of this invention with pyriproxyfen; a mixture of a compound of this invention with pymetrozine; a mixture of a compound of this invention with amitraz; a mixture of a compound of this invention with Bacillus thuringiensis and a mixture of a compound of this invention with Bacillus thuringiensis delta endotoxin.

In certain instances, combinations with other invertebrate pest control compounds or agents having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management. Thus, compositions of the present invention can further comprise an biologically effective amount of at least one additional invertebrate pest control compounds or agents having a similar spectrum of control but a different mode of action. Contacting a plant genetically modified to express a plant protection compound (e.g., protein) or the locus of the plant with a biologically effective amount of a compound of invention can also provide a broader spectrum of plant protection and be advantageous for resistance management.

Invertebrate pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the compounds of this invention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled. Thus, the present invention further comprises a method for the control of foliar- and soil-inhabiting invertebrates and protection of agronomic and/or nonagronomic crops, comprising contacting the invertebrates or their environment with a biologically effective amount of one or more of the compounds of the invention, or with a composition comprising at least one such compound or a composition comprising at least one such compound and an effective amount of at least one additional biologically active compound or agent. A preferred method of contact is by spraying. Alternatively, a granular composition comprising a compound of the invention can be applied to the plant foliage or the soil. Compounds of this invention are effective in delivery through plant uptake by contacting the plant with a composition comprising a compound of this invention applied as a soil drench of a liquid formulation, a granular formulation to the soil, a nursery box treatment or a dip of transplants. Other methods of contact include application of a compound or a composition of the invention by direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others.

The compounds of this invention can be incorporated into baits that are consumed by the invertebrates or within devices such as traps and the like. Granules or baits comprising between 0.01-5% active ingredient, 0.05-10% moisture retaining agent(s) and 40-99% vegetable flour are effective in controlling soil insects at very low application rates, particularly at doses of active ingredient that are lethal by ingestion rather than by direct contact.

The compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use. A preferred method of application involves spraying a water dispersion or refined oil solution of the compounds. Combinations with spray oils, spray oil concentrations, spreader stickers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.

The rate of application required for effective control (i.e. “biologically effective amount”) will depend on such factors as the species of invertebrate to be controlled, the pest's life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.0001 kg/hectare may be sufficient or as much as 8 kg/hectare may be required. For nonagronomic applications, effective use rates will range from about 1.0 to 50 mg/square meter but as little as 0.1 mg/square meter may be sufficient or as much as 150 mg/square meter may be required. One skilled in the art can easily determine the biologically effective amount necessary for the desired level of invertebrate pest control.

The following Tests in the Biological Examples of the Invention demonstrate the efficacy of methods of the invention for protecting plants from specific arthropod pests. “Control efficacy” represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding. The pest control protection afforded by the compounds is not limited, however, to these species. See Index Table A for compound descriptions. The following abbreviations are used in the Index Table which follows: t is tertiary, n is normal, i is iso, s is secondary, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl and Bu is butyl; accordingly i-Pr is isopropyl, s-Bu is secondary butyl, etc. The abbreviation “Ex.” stands for “Example” and is followed by a number indicating in which example the compound is prepared.

INDEX TABLE A

Compound R³ R² R⁴, R⁵ R⁶ R⁷ m.p. (° C.)  1 i-Pr H 2-Me CF₃ CH₃ 200-204  2 (Ex. 1) i-Pr H 2-Me CF₃ Et 123-126  3 i-Pr H 2-Cl CF₃ CH₃ 233-235  4 t-Bu H 2-Me CF₃ Et 215-218  5 i-Pr H 2-Me CH₃ Ph 238-239  6 i-Pr H 2-Me CH₃ CH₃ 206-208  7 i-Pr H 2-Me CH₃ CH₂CF₃ 246-248  8 i-Pr H 2-Cl Et CF₃ 235-237  9 i-Pr H 2-Me CH₃ CH₃, R⁸ is Cl 205-207  10 i-Pr H 2-Me CH₃ 4-CF₃-Ph 256-258  11 i-Pr H 2-Me CH₃ 2-CF₃-Ph 204-206  12 t-Bu H 2-Me CH₃ Ph 236-238  13 i-Pr H 2-F CH₃ Ph 227-229  14 i-Pr H 5-F CH₃ Ph 209-211  15 i-Pr H 2-Cl CH₃ Ph 233-234  16 i-Pr H H CH₃ Ph 215-217  17 i-Pr H 2-NO₂ CH₃ Ph 236-237  18 i-Pr H 2-Cl CF₃ Ph 240-242  19 (Ex. 2) i-Pr H 2-Me CF₃ Ph 260-262  20 i-Pr H 2-I CH₃ Ph 250-251  21 i-Pr H 2-I CH₃ 2-CF₃-Ph 251-253  22 H H 2-Me CH₃ Ph 253-255  23 Et Et 2-Me CH₃ Ph 182-184  24 t-Bu H 2-Cl CF₃ Ph 232-234  25 i-Pr H 2-I CF₃ Ph 271-273  26 t-Bu H 2-I CF₃ Ph 249-250  27 i-Pr H 2-Me CH₃ t-Bu 210-211  28 i-Pr H 2-Br CF₃ Ph 257-259  29 i-Pr H 2-Br CH₃ Ph 246-247  30 i-Pr H 2-Me CF₃ 2-pyridinyl 237-238  31 i-Pr H 2,5-di-Cl CF₃ Ph >250  32 i-Pr, B is S H 2-Me CF₃ Ph 169-172  33 i-Pr H 2-Me CF₃ 2-Cl-Ph 208-209  34 i-Pr H 2-Cl CF₃ 2-Cl-Ph 234-235  35 i-Pr H 2-Me CF₃ 4-Cl-Ph 289-290  36 i-Pr H 2-Cl CF₃ 4-Cl-Ph 276-278  37 i-Pr H 2-Cl CF₃ 2-pyridinyl 239-240  38 i-Pr H 2-Me CF₃ 2-pyrimidinyl 205-208  39 i-Pr H 2-Me CF₃ 2-(3-CH₃-pyridinyl) 183-187  40 i-Pr H 2-Me CF₂CF₃ Ph 231-232  41 i-Pr H 2-Cl CF₂CF₃ Ph 206-207  42 t-Bu H 2-Cl CF₂CF₃ Ph 212-213  43 i-Pr H 2-Br CF₂CF₃ Ph 219-222  44 i-Pr H 2-Me CF₃ 3-Cl-Ph 278-280  45 i-Pr H 2-Cl CF₃ 3-Cl-Ph 272-273  46 i-Pr H 2-Me CF₃ 2-F-Ph 217-218  47 i-Pr H 2-Cl CF₃ 2-F-Ph 220-221  48 i-Pr H 2-Me CF₃ 4-F-Ph 269-270  49 i-Pr H 2-Cl CF₃ 4-F-Ph 279-280  52 i-Pr H 2-CF₃ CF₃ Ph 247-249  53 i-Pr H 2-Cl CF₃ i-Pr 255-258  54 i-Pr H 2-Me CF₃ 3-F-Ph 277-278  55 i-Pr H 2-Cl CF₃ 3-F-Ph 256-257  56 i-Pr H 2-Me CF₃ 2-CF₃-Ph 215-216  57 i-Pr H 2-Cl CF₃ 2-CF₃-Ph 230-231  58 i-Pr H 2-Me CF₃ 2-Br-Ph 207-208  59 i-Pr H 2-Cl CF₃ 2-Br-Ph 239-240  60 i-Pr H 2-OCH₃ CF₃ Ph 215-216  61 i-Pr H 5-Cl CF₃ 2-(3-CH₃-pyridinyl) 224-225  62 i-Pr H 5-Me CF₃ 2-(3-Cl-pyridinyl) 179-181  63 s-Bu H 2-Cl CF₃ Ph >240  64 c-Pr H 2-Cl CF₃ Ph >240  65 Et H 2-Cl CF₃ Ph >240  66 t-Bu H 2-CF₃ CF₃ Ph 230-233  67 Et H 2-CF₃ CF₃ Ph 246-249  68 CH(CH₃)CH₂SCH₃ H 2-CF₃ CF₃ Ph 215-217  69 CH(CH₃)CF₂OCH₃ H 2-CF₃ CF₃ Ph 220-223  70 i-Pr H 5-Cl CF₃ 2-(3-Cl-pyridinyl) 230-233  71 i-Pr H 5-Me CF₃ 2-thiazolyl 201-203  72 i-Pr H 5-Me CF₃ 2-pyrazinyl 252-253  73 i-Pr H 5-Me CF₃ 4-pyridinyl 224-228  74 i-Pr H 2-Me CF₃ i-Pr 236-243  75 i-Pr H 2-Me CF₃ 2-CH₃-Ph 211-212  76 i-Pr H 2-Cl CF₃ 2-CH₃-Ph 232-234  77 i-Pr H 2-Br CF₃ 2-Cl-Ph 247-248  78 t-Bu H 2-Me CF₃ 2-Cl-Ph 216-217  79 (Ex. 3) i-Pr H 2-Me CF₃ 2-(3-CF₃-pyridinyl) 227-230  80 CH₂CH₂Cl H 2-Cl CF₃ Ph 237-242  81 CH₂CH₂CH₂Cl H 2-Cl CF₃ Ph 233-239  82 CH(CH₃)CO₂CH₃ H 2-Cl CF₃ Ph 221-222  83 CH(i-Pr)CO₂CH₃ H 2-Cl CF₃ Ph 212-213 (S configuration)  84 i-Pr H 2-Me CF₃ 2,6-di-Cl-Ph 267-268  85 i-Pr H 2-Cl CF₃ 2,6-di-Cl-Ph 286-287  86 i-Pr H 2-Me Br Ph 253-255  87 i-Pr H 2-Cl Br Ph 247-248  88 i-Pr H 2-Me CF₃ i-Bu 205-210  89 i-Pr H 2-Me CF₃ CH₂Ph 235-237  90 i-Pr H 2-Me CF₃ 2-(3-CH₃O-pyridinyl) 221-222  91 i-Pr H 2-Me CF₃ 3-pyridinyl 260-261  92 i-Pr H 2-Me CF₃ 4-quinolinyl >260  93 i-Pr H 2-Me CN 2-(3-Cl-pyridinyl) 203-204  94 i-Pr H 2-Me CF₃ 2,4-di-F-Ph 245-246  95 i-Pr H 2-Cl CF₃ 2,4-di-F-Ph 252-253  96 i-Pr H 2-Me CF₃ 2-Et-Ph 207-209  97 i-Pr H 2-Cl CF₃ 2-Et-Ph 221-222  98 i-Pr H H CF₃ 2-Cl-Ph 206-207  99 t-Bu H H CF₃ 2-Cl-Ph 197-198 100 CH(CH₃)CH₂OCH₃ H H CF₃ 2-Cl-Ph 145-148 101 CH(CH₃)CH₂SCH₃ H H CF₃ 2-Cl-Ph 158-160 102 CH(CH₃)CH₂SCH₃ H 2-Cl CF₃ Ph 184-186 103 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃ Ph 217-218 104 n-Pr H 2-Cl CF₃ Ph 247-248 105 i-Bu H 2-Cl CF₃ Ph 244-245 106 CH₃ H 2-Cl CF₃ Ph >250 107 i-Pr Me 2-Cl CF₃ Ph 193-194 108 CH₂C≡CH H 2-Cl CF₃ Ph >250 109 CH₂CH═CH₂ H 2-Cl CF₃ Ph 248-249 110 CH₂(2-furanyl) H 2-Cl CF₃ Ph 246-247 113 i-Pr H 2-Me CF₃ 4-(3,5-di-Cl-pyridinyl) 239-242 114 i-Pr H 2-Cl CF₃ 4-(3,5-di-Cl-pyridinyl) 229-231 115 CH(CH₃)CH₂SCH₃ H 2-Me CF₃ 2-Cl-Ph 194-195 116 CH(CH₃)CH₂OCH₃ H 2-Me CF₃ 2-Cl-Ph 181-183 117 s-Bu H 2-Me CF₃ 2-Cl-Ph 199-200 118 c-Pr H 2-Me CF₃ 2-Cl-Ph 234-235 119 n-Pr H 2-Me CF₃ 2-Cl-Ph 222-223 120 i-Bu H 2-Me CF₃ 2-Cl-Ph 235-237 121 Me H 2-Me CF₃ 2-Cl-Ph 242-243 122 i-Pr Me 2-Me CF₃ 2-Cl-Ph 90-93 123 CH₂C≡CH H 2-Me CF₃ 2-Cl-Ph 215-216 124 Et H 2-Me CF₃ 2-Cl-Ph 228-229 125 CH₂CH═CH₂ H 2-Me CF₃ 2-Cl-Ph 227-228 126 CH₂(2-furanyl) H 2-Me CF₃ 2-Cl-Ph 218-219 127 CH(CH₃)CH₂SCH₃ H 2-Me CF₃ Ph 179-180 128 CH(CH₃)CH₂OCH₃ H 2-Me CF₃ Ph 219-220 129 s-Bu H 2-Me CF₃ Ph 244-245 130 c-Pr H 2-Me CF₃ Ph >250 131 n-Pr H 2-Me CF₃ Ph 238-239 132 i-Bu H 2-Me CF₃ Ph 237-238 133 Me H 2-Me CF₃ Ph 263-265 134 i-Pr Me 2-Me CF₃ Ph 178-179 135 CH₂C≡CH H 2-Me CF₃ Ph 153-154 136 Et H 2-Me CF₃ Ph 244-245 137 CH₂CH═CH₂ H 2-Me CF₃ Ph 240-241 138 CH₂(2-furanyl) H 2-Me CF₃ Ph 245-246 139 i-Pr H 2-OCHF₂ CF₃ 2-Cl-Ph 200-201 140 i-Pr H 2-OCH₃ CF₃ 2-Cl-Ph 206-207 141 i-Pr H 2-I CF₃ 2-Cl-Ph 253-256 142 i-Pr H 2-Me Br 2-Cl-Ph 147-150 143 i-Pr H 2-Cl Br 2-Cl-Ph 246-247 144 i-Pr H 2-Me CF₃ 2-CH₃O-Ph 218-219 145 i-Pr H 2-Cl CF₃ 2-CH₃O-Ph 243-244 146 i-Pr H 2-Me CF₃ 1-isoquinolinyl 252-253 147 CH(CH₃)CH₂SCH₃ H 2-Cl CF₃ 2-Cl-Ph 217-218 148 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃ 2-Cl-Ph 207-208 149 s-Bu H 2-Cl CF₃ 2-Cl-Ph 216-217 150 c-Pr H 2-Cl CF₃ 2-Cl-Ph 261-262 151 n-Pr H 2-Cl CF₃ 2-Cl-Ph 231-232 152 i-Bu H 2-Cl CF₃ 2-Cl-Ph 255-256 153 Me H 2-Cl CF₃ 2-Cl-Ph 233-235 154 i-Pr Me 2-Cl CF₃ 2-Cl-Ph 127-128 155 CH₂C≡CH H 2-Cl CF₃ 2-Cl-Ph 226-227 156 Et H 2-Cl CF₃ 2-Cl-Ph 244-246 157 CH₂CH═CH₂ H 2-Cl CF₃ 2-Cl-Ph 235-236 158 CH₂(2-furanyl) H 2-Cl CF₃ 2-Cl-Ph 207-208 160 i-Pr H C≡CH CF₃ 2-Cl-Ph 228-230 161 i-Pr H 2-Cl C≡CH 2-Cl-Ph 219-222 162 i-Pr H 2-Me H H, R⁸ is CH₃ 220-223 163 i-Pr H 2-Me CH₃ Ph, R⁸ is Cl 209-210 164 i-Pr, B is S H 2-Cl CF₃ Ph 169-174 165 i-Pr H 2-Me CF₃ 2,6-di-F-Ph 223-225 166 i-Pr H 2-Me CF₃ 2-Cl-6-F-Ph 203-206 167 i-Pr H 2-Cl CF₃ 2-Cl-6-F-Ph 218-221 168 i-Pr H 2-Me-4-Br CF₃ 2-F-Ph 232-233 169 t-Bu H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 250-251 170

H 2-Cl CF₃ 2-(3-Cl-pyridinyl) >250 171 Et Et 2-Cl CF₃ 2-Cl-Ph 252-253 172 Me Me 2-Cl CF₃ 2-Cl-Ph 234-235 173 Et Et 2-Me CF₃ 2-Cl-Ph 237-238 174 Me Me 2-Me CF₃ 2-Cl-Ph 225-226 176 i-Pr H 2-Cl CF₃ 2-pyrazinyl 242-243 177 t-Bu H 2-Me-4-Br CF₃ 2-Cl-Ph >260 178 CH(CH₃)CH₂OCH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 176-177 179 CH(CH₃)CH₂SCH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 196-197 180 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 197-198 181 CH(CH₃)CH₂SCH₃ H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 202-203 182 i-Pr H 2-Me CF₃ 2-I-Ph 221-222 183 i-Pr H 2-Cl CF₃ 2-I-Ph 238-240 184 i-Pr H 2-Me CF₃ 2-(HC≡C)-Ph 215-217 185 i-Pr H 2-Cl CF₃ 2-(HC≡C)-Ph 244-246 186 i-Pr H 2-Me CF₃ 2-Cl-4-F-Ph 203-205 187 i-Pr H 2-Cl CF₃ 2-Cl-4-F-Ph 218-219 188 Et Et 2-Me CF₃ 2-Cl-Ph 243-247 189 i-Pr H 2-Me CF₃ 2,6-di-Me-Ph 259-260 190 i-Pr H 2-Cl CF₃ 2,6-di-Me-Ph 268-269 191 i-Pr H 2-Me CF₃ 2,6-di-Cl-4-CN-Ph * 192 i-Pr H 2-Me CF₃ 2-CN-Ph 225-235 193 i-Pr H 2-Me CF₃ 2-(CF₃O)-Ph 214-215 194 i-Pr H 2-Cl CF₃ 2-(CF₃O)-Ph 223-224 195 i-Pr H 2-Me CF₃ 2-Br-4-F-Ph 202-203 196 i-Pr H 2-Cl CF₃ 2-Br-4-F-Ph 222-223 197 i-Pr H 2-Me CF₃ 2-(3-Me-pyrazinyl) 205-207 198 Me H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-220 199 CH₂C≡CH H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 197-198 200 Me H 2-Me CF₃ 2-(3-Cl-pyridinyl) 193-196 201 Et H 2-Me CF₃ 2-(3-Cl-pyridinyl) 204-206 202 CH₂C≡CH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 177-178 203 i-Pr H 2-Me CF₃ 4-(8-Cl-quinolinyl) >250 204 i-Pr H 2-Me CF₃ 4-(2-Me-quinolinyl) >250 205 i-Pr H 2-Cl CF₃ 4-(2-Me-quinolinyl) >250 206 i-Pr H 2-Me CF₃ 4-(7-Cl-quinolinyl) >250 207 i-Pr H 2,4-Br₂ CF₃ 2-Cl-Ph 233-234 208 i-Pr H 2-Br Br 2-Cl-Ph 255-258 209 Me H 2-Me Br 2-Cl-Ph 236-237 210 t-Bu H 2-Cl Br 2-Cl-Ph 260-261 211 Et H 2-Me Br 2-Cl-Ph 254-255 212 t-Bu H 2-Me Br 2-Cl-Ph 259-260 213 c-Bu H 2-Cl CN 2-(3-Cl-pyridinyl) 177-180 214 (Ex. 4, 5) i-Pr H 2-Me CF₃ 2-(3-Cl-pyridinyl) 237-239 215 i-Pr H 2-Me CF₃ 4-(6-Cl-quinolinyl) >250 216 Me Me 2-Me CF₃ 4-(6-Cl-quinolinyl) >250 218 i-Pr H 2-Cl CN 2-(3-Cl-pyridinyl) 195-200 219 t-Bu H 2-Cl CN 2-(3-Cl-pyridinyl) >250 220 Et H 2-Cl CN 2-(3-Cl-pyridinyl) 200-205 221 i-Pr H 2-Cl CF₃ 2-(3-Me-pyrazinyl) 225-230 222 t-Bu H 2-Cl CF₃ 2-(3-Me-pyrazinyl) 235-240 223 Et H 2-Cl CF₃ 2-(3-Me-pyrazinyl) 210-220 224 i-Pr H 2-Me CF₃ 3-(2-Cl-pyridinyl) * 225 i-Pr H 2-Cl CF₃ 2,3-di-Cl-Ph 217-219 226 t-Bu H 2-Cl CF₃ 2,3-di-Cl-Ph 254-256 227 i-Pr H 2-Me CF₃ 2,3-di-Cl-Ph 208-209 228 t-Bu H 2-Me CF₃ 2,3-di-Cl-Ph 232-233 229 t-Bu H 2-Me-4-Br Br 2-Cl-Ph 239-241 230 Me H 2-Me-4-Br Br 2-Cl-Ph 150-152 231 Et H 2-Me-4-Br Br 2-Cl-Ph 223-225 232 i-Pr H 2-Me-4-Br Br 2-Cl-Ph 197-198 233 Me H 2-Me CF₃ 2-F-Ph 245-247 234 CH₂C≡CH H 2-Me CF₃ 2-F-Ph 222-227 235 Me Me 2-Cl CF₃ 2-Cl-Ph 234-236 236 CH₂C≡CH H 2-Me-4-Br Br 2-Cl-Ph 187-188 237 i-Pr H 2-Cl CF₃ 2-(3-Me-pyridinyl) 224-225 238 i-Pr H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 230-233 239 i-Pr H 2-Me CF₃ 2-pyrazinyl 252-253 240 i-Pr H 2-Me CF₃ 2-thiazolyl 201-203 241 i-Pr H 2-Me CF₃ 4-pyridinyl 224-228 242 i-Pr H 2-Me CF₃ 2-(3-Cl-pyridinyl) 249-250 243 i-Pr H 2-Me CF₃ Ph, R⁸ is CH 246-248 244 Me Me 2-Me CF₃ 2-Cl-Ph 234-235 245 i-Pr H 2-Me CF₃ CH═CHCH₃ 225-228 246 i-Pr H 2-Me CF₃ 2-Cl-6-Me-Ph 247 i-Pr H 2-Cl CF₃ 2-Cl-6-Me-Ph 248 i-Pr H 2-Cl CF₃ 2-Cl-6-Me-Ph * 249 i-Pr H 2-Cl CF₃ 2,6-di-Cl-4-CN-Ph * 250 i-Pr H 2-Cl CF₃ 2-Cl-4-CN-Ph * 251 i-Pr H 2-Cl CN Ph * 252 i-Pr H 2-Me CF₃ 4-CN-Ph 271-272 253 i-Pr H 2-Me CF₃ 3-CN-Ph 263-264 254 i-Pr H 2-Me CF₃ 2-Cl-4-CN-Ph * 255 i-Pr H 2-Me CN Ph * 256 i-Pr H 2-Cl CF₃ 3-CN-Ph * 257 i-Pr H 2-Me CF₃ 2-Me-4-F-Ph 204-206 258 i-Pr H 2-Cl CF₃ 2-Me-4-F-Ph 212-213 259 i-Pr H 2-Me CF₃ 2,4-di-Me-Ph 189-190 260 t-Bu H 2-Me CF₃ 2,4-di-Me-Ph 197-198 261 t-Bu H 2-Cl CF₃ 2,4-di-Me-Ph 234-235 262 i-Pr H 2-Me CF₃ n-Bu, R⁸ is Cl 95-98 263 Me H 2-Cl CF₃ 4-(7-Cl-quinolinyl) >250 264 Et H 2-Cl CF₃ 4-(7-Cl-quinolinyl) >250 265 CH₂CH═CH₂ H 2-Cl CF₃ 4-(7-Cl-quinolinyl) >250 266 i-Pr H 2-Cl CF₃ 4-(8-Cl-quinolinyl) >250 267 i-Pr H 2-Me CF₃ 2-(3-CN-pyridinyl) 237-239 268 i-Pr H 2-Me CF₃ 1-(6-Cl-isoquinolinyl) >250 269 t-Bu H 2-Me CF₃ 1-(6-Cl-isoquinolinyl) 227-229 270 Me Me 2-Me CF₃ 1-(6-Cl-isoquinolinyl) >250 271 i-Pr H 2-Me CF₃ 2-Cl-4-CN-6-Me-Ph * 272 i-Pr H 2-Me-4-Br Br 2-Cl-Ph 187-188 273 CH₂CH(OCH₃)₂ H 2-Me CF₃ 2-Cl-Ph 205-207 274 CH₂CH(OCH₃)₂ Me 2-Me CF₃ 2-Cl-Ph 185-190 275 CH₂CH₂CH(OCH₃)₂ H 2-Me CF₃ 2-Cl-Ph 85-90 276 Me H 2-Me CF₃ 2,6-di-Cl-Ph 280-282 277 Et H 2-Me CF₃ 2,6-di-Cl-Ph 274-275 278 t-Bu H 2-Me CF₃ 2,6-di-Cl-Ph 285-286 279 t-Bu H 2-Cl CF₃ 2,6-di-Cl-Ph 290-291 280 i-Pr H 2-Me H 2-Cl-Ph * 281 i-Pr H 2-Me H 2-Me-Ph * 282 i-Pr H 2-Me H 2-F-Ph * 283 i-Pr H 2-Me Br 2-(3-Cl-pyridinyl) 206-209 284 CH₂CH₂CN H 2-Me CF₃ 2-Cl-Ph 189-195 285 i-Pr H 2-Me CN 2-Cl-Ph * 286 i-Pr H 2-Me CF₃ 2-(3-CH₃O-pyrazinyl) 195-200 287 i-Pr H 2-Me Br 2,6-di-Cl-Ph 265-267 288 t-Bu H 2-Me Br 2,6-di-Cl-Ph 282-284 289 i-Pr H 2-Cl Br 2,6-di-Cl-Ph 277-279 290 t-Bu H 2-Cl Br 2,6-di-Cl-Ph 296-298 291 i-Pr H 2-Me Br 2-Cl-4-F-Ph 236-238 292 t-Bu H 2-Me Br 2-Cl-4-F-Ph 249-250 293 i-Pr H 2-Cl Br 2-Cl-4-F 176-177 294 t-Bu H 2-Cl Br 2-Cl-4-F-Ph 257-258 295 i-Pr H 2-I Br 2-Cl-4-F 227-229 296 c-Bu H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 230-231 297 i-Pr H 2-Cl Br 2-(3-Cl-pyridinyl) 231-234 298 t-Bu H 2-Cl Br 2-(3-Cl-pyridinyl) 245-248 299 Et H 2-Cl Br 2-(3-Cl-pyridinyl) 219-222 300 Et H 2-Me Br 2-(3-Cl-pyridinyl) 217-220 301 t-Bu H 2-Me Br 2-(3-Cl-pyridinyl) 237-240 302 CH₂CN H 2-Me Br 2-(3-Cl-pyridinyl) 227-229 303 t-Bu H 2-Me CN 2-(3-Cl-pyridinyl) 215-225 304 c-Bu H 2-Me CN 2-(3-Cl-pyridinyl) 105-115 305 c-Bu H 2-Me CF₃ 2-(3-Cl-pyridinyl) 187-190 306 c-pentyl H 2-Me CF₃ 2-(3-Cl-pyridinyl) 190-195 307 s-Bu H 2-Me CF₃ 2-(3-Cl-pyridinyl) 170-180 308 c-pentyl H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-222 309 s-Bu H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 210-220 313 i-Pr H 2-Me Cl 2-(3-Cl-pyridinyl) 204-206 314 t-Bu H 2-Me Cl 2-(3-Cl-pyridinyl) 210-213 315 t-Bu H 2-Cl Cl 2-(3-Cl-pyridinyl) 237-239 316 i-Pr H 2-Cl Cl 2-(3-Cl-pyridinyl) 159-162 317 CH(CH₃)₂CH₂CH₃ H 2-Me CN 2-(3-Cl-pyridinyl) 165-175 318 c-hexyl H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 250-260 319 CH(CH₃)₂CH₂CH₃ H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 200-210 320 i-Pr H 2,4-di-Me CF₃ 2-Cl-Ph 239-240 321 i-Pr H 2-Me CF₃ 2-Cl-5-CN-Ph * 322 i-Pr H 2-Me H 2-(3-Cl-pyridinyl) 111-115 323 i-Pr H 2-Me CF₃ 2-CO₂Me-Ph 324 i-Pr H 2-Me-4-Br CF₃ 2,6-di-Cl-Ph 230-233 325 t-Bu H 2-Me-4-Br CF₃ 2,6-di-Cl-Ph >250 326 Me H 2-Me-4-Br CF₃ 2,6-di-Cl-Ph 228-230 327 CH₂CN H 2-Me-4-Br CF₃ 2,6-di-Cl-Ph 228-230 328 i-Pr H 2,4-di-Cl CF3 2-Cl-Ph 223-224 329 i-Pr H 2-Me CF₃ 2-Cl-4-CF₃-6-Cl-Ph 206-207 330 i-Pr H 2-Me CF₃ 5-(1,3-di-Me-4-Cl-pyrazolyl) 231-232 331 i-Pr H 2-Me CF₃ 2-(4,6-di-Me-pyrimidinyl) 220-222 332 i-Pr H 2-Cl CF₃ 2-(4,6-di-Me-pyrimidinyl) 152-154 333 t-Bu H 2-Me CF₃ 2-(4,6-di-Me-pyrimidinyl) 124-127 334 t-Bu H 2-Cl CF₃ 2-(4,6-di-Me-pyrimidinyl) 179-182 335 i-Pr H 4-I CF₃ 2-Cl-Ph 218-219 336 i-Pr H 2-Me-4-OCH₃ CF₃ 2-(3-Cl-pyridinyl) 187-188 337 i-Pr H 2-Me CF₃ 2-F-4-Cl-5-(i-PrO)-Ph 214-216 338 CH₂CN H 2-Me Cl 2-(3-Cl-pyridinyl) 190-195 339 Et H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 217-219 340 i-Pr H 2-Me-4-Br CF₃ 2,3-di-Cl-Ph >250 341 i-Pr H 2-Me CF₃ 2,5-di-Cl-Ph >250 342 i-Pr H 2-Cl-4-Br CF₃ 2,3-di-Cl-Ph 251-253 343 CH₂CN H 2-Cl CF₃ 2,3-di-Cl-Ph 185-190 344 CH₂CH₂SCH₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 197-200 345 CH₂CH₂CH₂SCH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 185-190 346 CH₂(2-furanyl) H 2-Me CF₃ 2-(3-Cl-pyridinyl) 210-215 347 CH₂C(═CH₂)CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 225-229 348 CH₂CH₂OCH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 215-218 349 CH₂CH₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 210-212 350 CH₂CH₂Cl H 2-Me CF₃ 2-(3-Cl-pyridinyl) 206-216 351 CH₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 217-220 352 CH(CH₃)CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 110-115 353 CH₂CH(Br)CH₂Br H 2-Me CF₃ 2-(3-Cl-pyridinyl) 217-220 354 CH₂CO₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) >250 355 CH₂CH(OH)CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) >250 356 CH₂CH₂CH₂Cl H 2-Me CF₃ 2-(3-Cl-pyridinyl) 207-212 357 CH(CH₂OH)CH₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 173-176 358 i-Pr H 2-Me CF₃ 2-(5-CF₃-pyridinyl) 270-275 359 Et H 2-Me CF₃ 2-(3,6-di-Me-pyrazinyl) 210-215 360 i-Pr H 2-Me CF₃ 2-(3,6-di-Me-pyrazinyl) 215-220 361 t-Bu H 2-Me CF₃ 2-(3,6-di-Me-pyrazinyl) 265-270 362 Et H 2-Cl CF₃ 2-(3,6-di-Me-pyrazinyl) 214-217 363 i-Pr H 2-Cl CF₃ 2-(3,6-di-Me-pyrazinyl) 215-218 364 i-Pr H 2-Me OCH₃ 2-Cl-Ph 137-140 365 i-Pr H 2-Cl OCH₃ 2-Cl-Ph 155-158 366 i-Pr H 2-Me Me 2-Cl-Ph 151-154 367 i-Pr H 2-Cl Me 2,6-di-Cl-Ph 242-244 368 CH₂CH(OH)CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 123-125 369 CH₂CH(OH)CH₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 175-180 370 CH₂CN H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 142-143 371 c-Pr H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 213-214 372 CH₂CN H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 201-202 373 i-Pr H 2,6-di-Me CF₃ 2-(3-Cl-pyridinyl) 204-205 374 t-Bu H 2,6-di-Me CF₃ 2-(3-Cl-pyridinyl) 242-243 375 t-Bu H 2-Me CF₃ 2-(5-CF₃-pyridinyl) 220-230 376 C(CH₃)₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 205-210 377 CH₂CH₂F H 2-Me CF₃ 2-(3-Cl-pyridinyl) 127-130 378 i-Pr H 2-Me CF₃ 2-(4-Me-pyrimidinyl) 196-197 379 i-Pr H 2-Cl CF₃ 2-(4-Me-pyrimidinyl) 208-210 380 t-Bu H 2-Me CF₃ 2-(4-Me-pyrimidinyl) 180-182 381 t-Bu H 2-Cl CF₃ 2-(4-Me-pyrimidinyl) 182-184 382 s-Bu H 2-Me CF₃ 2-(3-Et-pyrazinyl) 160-165 383 Et H 2-Me CF₃ 2-(3-Et-pyrazinyl) 185-190 384 i-Pr H 2-Me CF₃ 2-(3-Et-pyrazinyl) 180-183 385 CH₂CF₂CF₃ H 2-Cl CF₃ 2-Cl-Ph 258-260 386 t-Bu H 2-Me CF₃ 2-(3-Et-pyrazinyl) 180-185 387 CH₂CF₃ H 2-Cl CF₃ 2-Cl-Ph 262-264 388 CH₂CN H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 192-193 389 CH(CH₃)CH₂OH H 2-Me CF3 2-Cl-Ph 203-205 390 i-Pr H 2-Me Cl 2-Cl-Ph 207-209 391 i-Pr H 2-Cl Cl 2-Cl-Ph 236-237 392 i-Pr H 2-Me I 2-Cl-Ph 225-226 393 i-Pr H 2-Cl I 2-Cl-Ph 251-253 394 CH(CH₃)CH₂Cl H 2-Me CF₃ 2-Cl-Ph 212-214 395 H H 2-Me CF₃ 2-(3-Cl-pyridinyl) 217-220 396 i-Pr H 2-Cl CF₃ 4-(5,6-di-Me-pyrimidinyl) 218-220 397 t-Bu H 2-Cl CF₃ 4-(5,6-di-Me-pyrimidinyl) 212-214 398 i-Pr H 2-Cl CF₃ 4-(2,5,6-tri-Me-pyrimidinyl) 162-164 399 i-Pr H 2-Me CF₃ 4-(5,6-di-Me-pyrimidinyl) 162-164 400 CH₂CH(OH)CH₃ H 2-Me CF₃ 2-Cl-Ph 207-209 401 H H 2-Me CF₃ 2-Cl-Ph 230-232 402 CH₂CH(Cl)CH₃ H 2-Me CF₃ 2-Cl-Ph 230-232 403 CH₂CH₂CN H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-217 404 CH₂CH₂F H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 212-214 405 CH₂CH₂CN H 2-Cl CF₃ 2-Cl-Ph * 406 i-Pr H 2-Me-4-Br CN 2-(3-Cl-pyridinyl) * 407 CH₂CN H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 211-213 408 i-Pr H 2-Me CF3 2,5-di-F-Ph 179-181 409 i-Pr H 2,4-di-Br CN 2-(3-Cl-pyridinyl) * 410 t-Bu H 2,4-di-Br CN 2-(3-Cl-pyridinyl) 145-147 411 Me H 2,4-di-Br CN 2-(3-Cl-pyridinyl) 165-168 412 Et H 2,4-di-Br CN 2-(3-Cl-pyridinyl) 179-181 413 Me H 2-Me-4-Br Me 2-(3-Cl-pyridinyl) 141-143 414 t-Bu H 2-Me-4-Br Me 2-(3-Cl-pyridinyl) 161-163 415 i-Pr H 2-Me-4-Br Me 2-(3-Cl-pyridinyl) 141-143 416 Et H 2-Me-4-Br Me 2-(3-Cl-pyridinyl) 161-163 417 i-Pr H 2-Me Me 2-(3-Cl-pyridinyl) 193-195 418 Me H 2-Me Me 2-(3-Cl-pyridinyl) 194-196 419 i-Pr H 2-Me-4-Cl CN 2-(3-Cl-pyridinyl) 188-190 420 t-Bu H 2-Me-4-Cl CN 2-(3-Cl-pyridinyl) 148-151 421 Me H 2-Me-4-Cl CN 2-(3-Cl-pyridinyl) 182-184 422 Me H 2-Me Br 2-(3-Cl-pyridinyl) 210-212 423 H H 2-Cl CF₃ 2-Cl-Ph 203-205 424 H H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 243-245 425 t-Bu H 2-Me CF₃ 5-(1,3-di-Me-4-Cl-pyrazolyl) 220-221 426 i-Pr H 2-Cl CF₃ 5-(1,3-di-Me-4-Cl-pyrazolyl) 264-266 427 t-Bu H 2-Cl CF₃ 5-(1,3-di-Me-4-Cl-pyrazolyl) 231-232 428 CH₂CN H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 149-150 429 i-Pr H 2-Me-4-Cl Cl 2-Cl-Ph 180-181 430 i-Pr H 2-Me-4-Br Br 2,6-di-Cl-Ph 238-239 431 i-Pr H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 170-171 432 t-Bu H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 167-169 433 Me H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 162-164 434 H H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 235-237 435 Me H 5-Cl CF₃ 2-(3-Cl-pyridinyl) 207-208 436 CH₂CN H 5-Cl CF₃ 2-(3-Cl-pyridinyl) 178-179 437 Me H 5-Me CF₃ 2-(3-Cl-pyridinyl) 166-167 438 CH₂CN H 5-Me CF₃ 2-(3-Cl-pyridinyl) 191-192 439 H H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 243-244 440 i-Pr H 2-Me CF₃ 4-pyrimidinyl 441 i-Pr H 2-Cl CF₃ 4-pyrimidinyl 442 t-Bu H 2-Me CF₃ 4-pyrimidinyl 443 t-Bu H 2-Cl CF₃ 4-pyrimidinyl 444 i-Pr H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 173-175 445 t-Bu H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 149-150 446 Me H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 164-166 447 H H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 201-203 448 H H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 240-242 449 H H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 223-225 450 i-Pr H 2-Me CF₃ 4-(5-Cl-pyrimidinyl) 451 t-Bu H 2-Me CF₃ 4-(5-Cl-pyrimidinyl) 452 t-Bu H 2-Cl CF₃ 4-(5-Cl-pyrimidinyl) 453 c-Pr H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 224-228 454 CH₂CN H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 232-234 455 CH₂CN H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 221-222 456 Me H 2,4-di-Cl CF₃ 2-Cl-Ph 232-233 457 Et H 2,4-di-Cl CF₃ 2-Cl-Ph 247-248 458 t-Bu H 2,4-di-Cl CF₃ 2-Cl-Ph 223-224 459 CH₂CN H 2,4-di-Cl CF₃ 2-Cl-Ph 229-231 460 i-Pr H 2-Me CF₃ 5-(1-Me-pyrazolyl) 240-241 461 t-Bu H 2-Me CF₃ 5-(1-Me-pyrazolyl) 233-234 462 i-Pr H 2-Cl CF₃ 5-(1-Me-pyrazolyl) 247-248 463 t-Bu H 2-Cl CF₃ 5-(1-Me-pyrazolyl) 262-263 464 i-Pr H 2-Me CF₃ 4-(2,6-di-Me-5-Cl-pyrimidinyl) 465 i-Pr H 2-Cl CF₃ 4-(2,6-di-Me-5-Cl-pyrimidinyl) 466 t-Bu H 2-Me CF₃ 4-(2,6-di-Me-5-Cl-pyrimidinyl) 467 t-Bu H 2-Cl CF₃ 4-(2,6-di-Me-5-Cl-pyrimidinyl) 468 Et H 2-Me Cl 2-(3-Cl-pyridinyl) 220-221 469 Me H 2-Me Cl 2-(3-Cl-pyridinyl) 217-218 470 CH₂C≡CH H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 199-201 471 CH₂C≡CH H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 219-221 472 H H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 231-233 473 H H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 245-247 474 CH₂C≡CH H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 166-168 475 H H 2-Me Cl 2-(3-Cl-pyridinyl) 243-244 476 H H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 241-242 477 CH₂CN H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 225-226 478 CH₂C≡CH H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 218-220 479 H H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 224-225 480 H H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 250-252 481 i-Pr H 2-Me-4-Cl CF₃ 2-(3-Me-pyridinyl) 228-229 482 Me H 2-Me-4-Cl CF₃ 2-(3-Me-pyridinyl) 226-227 483 t-Bu H 2-Me CF₃ 5-(1-Me-4-Cl-pyrazolyl) 216-217 484 i-Pr H 2-Me CF₃ 5-(1-Me-4-Cl-pyrazolyl) 220-221 485 i-Pr H 2-Me-4-(HOCH₂) CF₃ 2-(3-Cl-pyridinyl) 199-201 486 CH₂C≡CH H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 200-202 487 i-Pr, B is S H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 214-217 488 i-Pr H 2-Me-4-CO₂Me CF₃ 2-(3-Cl-pyridinyl) 204-206 489 i-Pr H 2-Me-4-CONHMe CF₃ 2-(3-Cl-pyridinyl) 168-170 490 CH(CH₃)Ph H H CF₃ Me 212-214 491 CH(CH₃)Ph H H CF₃ Et 202-203 492 CH₂CH₂N(i-Pr) H 2-Me CF₃ 2-Cl-Ph 188-190 494 i-Pr H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 197-198 495 i-Pr H 2-Me CF₃ 2-CH₂NHC(═O)CF₃-Ph * 496 i-Pr H 2-Me CF₃ 2-CH₂NH₂-Ph HCl * 497 (Ex. 6) i-Pr H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 196-197 498 i-Pr H 2-Me CF₃ 2,4-di-Cl-5-OCH₂C≡CH-Ph 246-249 499 t-Bu H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 223-225 500 (Ex. 7) Me H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 148-150 501 i-Pr H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 192-193 502 t-Bu H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 246-247 505 CH₂CH₂OCH₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 132-135 506 Me H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 162-163 507 OCH(CH₃)₂ H 2-Cl CF₃ 2-Cl-Ph 218-219 508 OCH(CH₃)₂ H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 205-206 509 OCH(CH₃)₂ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 210-211 510 OCH(CH₃)₂ H 2-Me CF₃ 2-Cl-Ph 196-198 511 i-Pr H 2-Me CF₃ 2-CONHMe-Ph * 512 Et H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 188-189 513 i-Pr H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 200-201 514 t-Bu H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 170-172 515 Me H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 155-157 516 Et H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 201-202 517 t-Bu H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 247-248 518 Et H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 192-193 519 i-Pr H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 179-180 520 i-Pr H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 185-187 521 i-Pr H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 235-236 522 Et H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 216-217 523 i-Pr H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 188-189 524 t-Bu H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 148-149 525 Me H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 208-210 526 i-Pr H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 127-128 527 t-Bu H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 159-160 528 Et H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 224-225 529 Me H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 208-209 530 (Ex. 10) i-Pr H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 159-161 531 (Ex. 11) Me H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 162-164 532 t-Bu H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 159-161 533 i-Pr H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 162-163 534 Me H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 166-168 535 t-Bu H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 210-212 536 i-Pr H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 188-190 537 Me H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 179-180 538 Me H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 147-149 539 i-Pr H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 200-202 540 t-Bu H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 143-145 541 Me H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 171-173 542 Me H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 222-223 543 (Ex. 8) i-Pr H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 142-144 544 (Ex. 9) Me H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 175-177 545 t-Bu H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 163-165 546 i-Pr H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 152-153 547 Me H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 140-141 548 t-Bu H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 215-221 549 Me H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 199-200 550 i-Pr H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 197-199 551 Me H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 188-190 552 t-Bu H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 194-196 553 Et H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 192-194 554 i-Pr H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 197-199 555 Me H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 205-206 556 t-Bu H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 172-173 557 Et H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 206-208 558 Et H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 199-200 559 Et H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 163-164 560 Et H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 199-200 561 t-Bu H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 242-243 562 Et H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 194-195 563 Me H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 213-214 564 Et H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 212-213 565 t-Bu H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 142-143 566 Me H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 214-215 567 Et H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 204-205 568 i-Pr H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 206-208 569 Et H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 192-194 570 i-Pr H 2-Me-4-F Cl 2-(3-Cl-pyridinyl) 184-186 571 Me H 2-Me-4-F Cl 2-(3-Cl-pyridinyl) 180-182 572 Et H 2-Me-4-F Cl 2-(3-Cl-pyridinyl) 163-165 573 t-Bu H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 224-225 574 t-Bu H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 124-125 575 Et H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 196-197 576 Me H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 245-246 577 Et H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 214-215 578 Et H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 194-196 579 Me H 2-Me-4-I Br 2-(3-Cl-pyridinyl) 229-230 580 i-Pr H 2-Me-4-I Br 2-(3-Cl-pyridinyl) 191-192 581 Me H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 249-250 582 Me H 2-Me-4-I Cl 2-(3-Cl-pyridinyl) 233-235 583 Et H 2-Me-4-I Cl 2-(3-Cl-pyridinyl) 196-197 584 i-Pr H 2-Me-4-I Cl 2-(3-Cl-pyridinyl) 189-190 585 t-Bu H 2-Me-4-I Cl 2-(3-Cl-pyridinyl) 228-229 586 Me H 2-Me-4-Cl I 2-(3-Cl-pyridinyl) 208-209 587 i-Pr H 2-Me-4-Cl I 2-(3-Cl-pyridinyl) 183-184 588 H H 2-Me-4-Cl I 2-(3-Cl-pyridinyl) 228-230 589 Me H 2-Me-4-Cl Br 2-Cl-4-F-Ph 250-251 590 H H 2-Me-4-Cl Br 2-Cl-4-F-Ph 229-229 591 i-Pr H 2-Me-4-Cl Br 2-Cl-4-F-Ph 189-190 592 t-Bu H 2-Me-4-Cl Br 2-Cl-4-F-Ph 247-249 593 i-Pr H 2-Me-4-NO₂ CF₃ 2-Cl-Ph * 594 Ph H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 243-244 595 2-Me-Ph H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 249-251 596 i-Pr H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) 170-172 597 i-Pr H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 598 Me, B is S H 2-Me CF₃ 2-Cl-Ph 164-167 599 i-Pr H 2-NO₂ CF₃ 2-Cl-Ph * 600 i-Pr H 2-Me-4-Cl OCHF₂ 2-Cl-Ph 177-179 601 Me Me 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 151-152 602 CH(CH₃)CH₂OCH₃ H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 162-163 603 CH(CH₃)CH₂SCH3 H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 174-175 604 CH(CH₃)CH₂OH H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 148-149 605 i-Pr, R1 is Me H 2-Me Br 2-(3-Cl-pyridinyl) 223-225 606 i-Pr, R1 is Me H 2-Me Cl 2-(3-Cl-pyridinyl) 223-225 607 i-Pr, R1 is Me H 2-Me CF₃ 2-(3-Cl-pyridinyl) 218-219 608 i-Pr, B is S H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 231-235 609 N(CH₃)₂ H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 149-151 611 N(Me)₂ H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 185-188 612 i-Pr H 2-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 221-222 613 t-Bu H 2-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 217-218 614 CH(CH₃)CH₂CO₂Et H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 113-115 615 2-pyridinyl H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 244-245 616 2-(3-Me-pyridinyl) H 2-Me-4-Br CF₃ 2-(3-Me-pyridinyl) 182-183 619 Me, B is S H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 110-113 620 Me Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 207-208 621 Et Et 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 189-190 622 2-pyridinyl H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 233-234 623 2-(3-Me-pyridinyl) H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 202-203 624 Et Et 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 197-198 625 Me Me 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 142-143 626 CH(CH₃)CH₂SCH₃ H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 185-186 627 Et Et 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 209-210 628 i-Pr Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 133-135 629 Me Me 2,4-di-Br Br 2-(3-Cl-pyridinyl) 185-187 630 Et Et 2,4-di-Br Br 2-(3-Cl-pyridinyl) 204-205 631 CH(CH₃)CH₂SCH₃ H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 178-179 632 Et H 2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl) 209-211 633 i-Pr H 2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl) 179-181 634 Me H 2-Me-4-Br OCHF₂ 2-(3-Cl-pyridinyl) 190-192 635 Et H 2-Me-4-Cl OEt 2-Cl-Ph 163-165 636 i-Pr H 2-Me-4-Cl OEt 2-Cl-Ph 173-175 637 Me H 2-Me-4-Br OEt 2-Cl-Ph 155-158 638 Et Me 2,4-di-Br Br 2-(3-Cl-pyridinyl) 181-183 639 Et Me 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 162-163 640 Et Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 174-175 641 Me Me 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 216-218 642 Et Et 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 190-191 643 CH(CH₃)CH₂SCH₃ H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 182-183 644 Et Me 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 165-167 645 Et H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 646 Me Me 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 647 CH₂CH═CH₂ H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 648 n-Pr H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 649 CH(CH₃)CH₂SCH₃ H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 650 Me H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 651 t-Bu H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 652 CH₂CH₂N(Me)₂ H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) 193-195 653 CH₂CH₂N(Me)₃ ⁺I⁻ H 2-Me-4-NO2 CF₃ 2-(3-Cl-pyridinyl) >250 655 N(CH₃)₂ H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 146-148 656 N(CH₃)₂ H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 162-164 657 N(CH₃)₂ H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 208-209 658 Et H 2-Me-4-Cl OCH₂CF₃ 2-Cl-Ph 184-186 659 i-Pr H 2-Me-4-Cl OCH₂CF₃ 2-Cl-Ph 196-198 660 Me H 2-Me-4-Br OCH₂CF₃ 2-Cl-Ph 220-223 661 N(CH₃)₂ H 2-Me-4-NO2 CF₃ 2-(3-Cl-pyridinyl) * 662 H H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 240-242 663 n-Pr n-Pr 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 201-202 664 n-Pr H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 188-190 665 Et Et 2-Cl CF₃ 2-(3-Cl-pyridinyl) 242-243 666 n-Pr n-Pr 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 242-243 667 n-Pr H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 218-219 668 CH₂CO₂CH₂CH₃ Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 227-228 669 CH₂CO₂CH₂CH₃ Me 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 176-177 670 CH₂CO₂CH₂CH₃ Me 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 198-199 671 CH₂CO₂CH₃ H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 141-142 672 N(CH₃)₂ H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 136-137 673 Me Me 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 225-227 674 Et Et 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 228-229 675 CH₂CO₂CH₂CH₃ Me 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 219-220 676 Me H 2-Me-4-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 239-241 677 i-Pr H 2-Me-4-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 252-254 678 i-Pr H 2-Me-4-Br OEt 2-(3-Cl-pyridinyl) 208-211 679 Me H 2-Me-4-Br OEt 2-(3-Cl-pyridinyl) 212-215 680 i-Pr H 2-Me-4-Cl OEt 2-(3-Cl-pyridinyl) 191-193 681 Et H 2-Me-4-Cl OEt 2-(3-Cl-pyridinyl) 207-209 682 i-Pr H 2-Me-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 213-215 683 Me H 2-Me-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 206-208 684 i-Pr H 2-Me-4-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 211-213 685 Et H 2-Me-4-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 205-207 686 (Ex. 12) Me H 2-Me-4-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 195-197 687 Et H 2-Me-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 208-211 688 t-Bu H 2-Me-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 213-216 689 i-Pr H 2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl) 256-258 690 t-Bu H 2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl) 254-256 691 Me Me 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 228-229 692 i-Pr H 2-Me-4-Cl OCF₂CHF₂ 2-(3-Cl-pyridinyl) 189-192 693 Et H 2-Me-4-Cl OCF₂CHF₂ 2-(3-Cl-pyridinyl) 189-192 694 Me H 2-Me-4-Cl OCF₂CHF₂ 2-(3-Cl-pyridinyl) 162-165 695 i-Pr H 2-Me-4-Br OCF₂CHF₂ 2-(3-Cl-pyridinyl) 185-188 696 Et H 2-Me-4-Br OCF₂CHF₂ 2-(3-Cl-pyridinyl) 195-198 697 Me H 2-Me-4-Br OCF₂CHF₂ 2-(3-Cl-pyridinyl) 164-167 698 Me Me 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 238-239 699 Et Me 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 216-217 700 H H H CF₃ 2-(3-Cl-pyridinyl) 701 Et H 2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl) 249-251 702 i-Pr H 2,4-di-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 232-235 703 Me H 2,4-di-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 192-195 704 Me Me 2,4-di-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 132-135 705 i-Pr H 2,4-di-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 225-227 706 Me H 2,4-di-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 206-208 707 Me Me 2,4-di-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 175-177 708 Me H 2-Cl-4-Br Br 2-(3-Cl-pyridinyl) 226-227 709 Me Me 2-Cl-4-Br Br 2-(3-Cl-pyridinyl) 237-238 710 Me H 2-Cl-4-Br Cl 2-(3-Cl-pyridinyl) 228-229 711 Me Me 2-Cl-4-Br Cl 2-(3-Cl-pyridinyl) 263-237 712 CH₂C(Me)₂CH₂N-(Me)₂ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 197-200 713 Me H 2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl) 242-244 714 Et H 2-Me-4-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 252-254 715 t-Bu H 2-Me-4-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 259-260 716 i-Pr H 2,4-di-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 220-222 717 Me H 2,4-di-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 188-191 718 Me Me 2,4-di-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 203-205 719 Me H 2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl) 210-212 720 i-Pr H 2-Me-4-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 194-196 721 Me H 2-Me-4-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 181-183 722 Me H 3,4-di-F Cl 2-(3-Cl-pyridinyl) 202-203 723 Me Me 3,4-di-F Cl 2-(3-Cl-pyridinyl) 251-252 724 Me Me 2-Me-4-F Cl 2-(3-Cl-pyridinyl) 242-243 725 Me Me 2-Cl-4-F Br 2-(3-Cl-pyridinyl) 245-246 726 Me H 2-Cl-4-F Br 2-(3-Cl-pyridinyl) 217-218 727 t-Pr H 2-Cl-4-F Br 2-(3-Cl-pyridinyl) 168-169 728 Me Me 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 239-240 729 Me H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 248-249 730 i-Pr H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 169-170 731 Me Me 2-Cl-4-F CF₃ 2-(3-Cl-pyridinyl) 215-216 732 Me H 2-Cl-4-F CF₃ 2-(3-Cl-pyridinyl) 219-220 733 Me Me 2-Br-4-F Br 2-(3-Cl-pyridinyl) 235-236 734 Me H 2-Br-4-F Br 2-(3-Cl-pyridinyl) 238-239 735 i-Pr H 2-Br-4-F Br 2-(3-Cl-pyridinyl) 236-237 736 Me Me 2-Br-4-F Cl 2-(3-Cl-pyridinyl) 246-247 737 Me H 2-Br-4-F Cl 2-(3-Cl-pyridinyl) 233-234 738 i-Pr H 2-Br-4-F Cl 2-(3-Cl-pyridinyl) 153-154 739 i-Pr H 2-Me-4-Cl OCHMe₂ 2-(3-Cl-pyridinyl) 208-210 740 Me H 2-Me-4-Cl OCHMe₂ 2-(3-Cl-pyridinyl) 207-210 741 i-Pr H 2,4-di-Cl OCHMe₂ 2-(3-Cl-pyridinyl) 187-191 742 Me H 2,4-di-Cl OCHMe₂ 2-(3-Cl-pyridinyl) * 743 Me Me 2-Br-4-F CF₃ 2-(3-Cl-pyridinyl) 191-192 744 Me H 2-Br-4-F CF₃ 2-(3-Cl-pyridinyl) 228-229 745 i-Pr H 2-Br-4-F CF₃ 2-(3-Cl-pyridinyl) 224-226 746 Me Me 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 188-189 747 Me H 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 248-249 748 i-Pr H 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 252-253 749 Me Me 2-Br-4-Cl Cl 2-(3-Cl-pyridinyl) 147-148 750 Me H 2-Br-4-Cl Cl 2-(3-Cl-pyridinyl) 249-250 751 i-Pr H 2-Br-4-Cl Cl 2-(3-Cl-pyridinyl) 239-240 752 Me Me 2-Br-4-Cl CF₃ 2-(3-Cl-pyridinyl) 200-201 753 Me H 2-Br-4-Cl CF₃ 2-(3-Cl-pyridinyl) 158-159 754 i-Pr H 2-Br-4-Cl CF₃ 2-(3-Cl-pyridinyl) 250-250 755 Me Me 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 232-233 756 Me H 2-CF₃ CF₃ 2-(3-Cl-pyridinyl) 218-220 757 i-Pr H 2-CF₃ CF₃ 2-(3-Cl-pyridinyl) 242-246 758 Me Me 2-CF₃ CF₃ 2-(3-Cl-pyridinyl) 239-244 759 Me Me 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 210-211 760 Me Me 2,4-di-Me Cl 2-(3-Cl-pyridinyl) 223-224 761 Me Me 2,4-di-Me Br 2-(3-Cl-pyridinyl) 240-241 762 Me H 2-F Br 2-(3-Cl-pyridinyl) 215-216 763 i-Pr H 2-F Br 2-(3-Cl-pyridinyl) 213-215 764 i-Pr H 2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl) 254-256 765 Me Me 2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl) 229-231 766 Me H 2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl) 235-237 767 Me H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl), R⁸ is Cl 225-226 768 i-Pr H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl), R⁸ is Cl 230-232 769 Me Me 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl), R⁸ is Cl 194-196 770 i-Pr H 2-Me-4-Cl CF₃ 3-isoxazolyl 255-257 771 Me H 2,4-di-F Br 2-(3-Cl-pyridinyl) 197-198 772 Me Me 2,4-di-F Br 2-(3-Cl-pyridinyl) 218-222 773 Me H 2-F Cl 2-(3-Cl-pyridinyl) 185-187 774 Me H 2-F-4-Cl Br 2-(3-Cl-pyridinyl) 203-204 775 Me Me 2-F-4-Cl Br 2-(3-Cl-pyridinyl) 226-227 776 i-Pr H 2-F-4-Cl Br 2-(3-Cl-pyridinyl) 207-208 777 Me H 2-F-4-Cl Cl 2-(3-Cl-pyridinyl) 211-212 778 Me Me 2-F, 4-Cl Cl 2-(3-Cl-pyridinyl) 237-238 779 i-Pr H 2-Me-4-CN CF₃ 2-(3-Cl-pyridinyl) * 780 H H 2-F-4-Cl Cl 2-(3-Cl-pyridinyl) 116-117 781 Me H 2,4-di-F Cl 2-(3-Cl-pyridinyl) 159-160 782 Me Me 2,4-di-F Cl 2-(3-Cl-pyridinyl) 225-226 783 i-Pr H 2,4-di-F Cl 2-(3-Cl-pyridinyl) 201-202 784 H H 2,4-di-F Cl 2-(3-Cl-pyridinyl) 128-129 785 Et H 2-Me-4-Cl CF₃ 5-(1-CH₂CF₃-pyrazolyl) 172-174 786 Me H 2-Me-4-Cl CF₃ 5-(1-CH₂CF₃-pyrazolyl) 192-194 787 Me H 2,4-di-Cl F 2-(3-Cl-pyridinyl) * 788 Me H 2-F OCH₂CF₃ 2-(3-Cl-pyridinyl) 202-203 789 Me Me 2-F OCH₂CF₃ 2-(3-Cl-pyridinyl) 178-179 790 i-Pr H 2-F OCH₂CF₃ 2-(3-Cl-pyridinyl) 161-162 791 Me H 2-F-4-Br Br 2-(3-Cl-pyridinyl) 209-210 792 Me Me 2-F-4-Br Br 2-(3-Cl-pyridinyl) 225-226 793 i-Pr H 2-F-4-Br Br 2-(3-Cl-pyridinyl) 208-209 794 Me H 2-F-4-Br Cl 2-(3-Cl-pyridinyl) 209-210 795 Me Me 2-F-4-Br Cl 2-(3-Cl-pyridinyl) 244-245 796 Me Me 2-F-4-Br Cl 2-(3-Cl-pyridinyl) 207-208 797 Me H 2-F-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 210-211 798 Me Me 2-F-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 204-206 799 i-Pr H 2,4-di-Cl CF₃ 3-(4-Cl-5-Me-isoxazolyl) 204-205 800 Me H 2,4-di-Cl CF₃ 3-(4-Cl-5-Me-isoxazolyl) 131-132 801 i-Pr H 2-Me-4-Cl CF₃ 3-(4-Cl-5-Me-isoxazolyl) 188-189 802 Me H 2-Me-4-Cl CF₃ 3-(4-Cl-5-Me-isoxazolyl) 210-211 803 i-Pr H 2,4-di-Cl CF₃ 3-(4-Cl-isoxazolyl) 212-213 804 i-Pr H 2-Me-4-Cl CF₃ 3-(4-Cl-isoxazolyl) 232 805 Me H 2-Me-4-Cl CF₃ 3-(4-Cl-isoxazolyl) 190-191 806 Me H 2,4-di-Cl CF₃ 3-(4-Cl-isoxazolyl) 209-210 807 i-Pr H 4-Cl CF₃ 3-(4-Cl-isoxazolyl) 241-242 808 i-Pr H 2,4-di-Cl CF₃ 5-(1-CH₂CF₃-pyrazolyl) 212-214 809 H H 2,4-di-Cl F 2-(3-Cl-pyridinyl) * 810 i-Pr H 2,4-di-Cl F 2-(3-Cl-pyridinyl) * 811 Me Me 2,4-di-Cl F 2-(3-Cl-pyridinyl) * 812 H H 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 813 i-Pr H 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 814 Me H 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 815 Me Me 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 816 Me H 2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 242-244 817 Et H 2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 266-268 818 i-Pr H 2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 241-243 819 Me Me 2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 202-204 820 t-Bu H 2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 128-131 821 Me H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) * 822 H H 2-F-4-Br Br 2-(3-Cl-pyridinyl) 151-152 823 H H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 133-134 824 Me H 2,4-di-F F 2-(3-Cl-pyridinyl) 166-167 825 H H 2-F-4-Br Cl 2-(3-Cl-pyridinyl) 148-149 826 H H 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 134-136 827 Me Me 2,4-di-F F 2-(3-Cl-pyridinyl) 211-212 828 H H 2,4-di-F F 2-(3-Cl-pyridinyl) 115-117 829 i-Pr H 2,4-di-F F 2-(3-Cl-pyridinyl) 157-158 830 i-Pr H 2-Cl-4-I Cl 2-(3-Cl-pyridinyl) 192-195 831 i-Pr H 2,4-di-Cl OCH₃ 2-(3-Cl-pyridinyl) 191-194 832 Me H 2,4-di-Cl OCH₃ 2-(3-Cl-pyridinyl) 143-145 833 Me H 2-Me-4-Cl Br 2-(3-Cl-5-Br-pyridinyl) 216-219 834 Me H 2-F F 2-(3-Cl-pyridinyl) 217-218 835 Me H 2-Cl-4-F F 2-(3-Cl-pyridinyl) 207-208 836 Me Me 2-Cl-4-F F 2-(3-Cl-pyridinyl) 221-222 837 i-Pr H 2-C-4-F F 2-(3-Cl-pyridinyl) 166-167 838 H H 2-Cl-4-F F 2-(3-Cl-pyridinyl) 133-134 839 Me H 2-F-4-I Br 2-(3-Cl-pyridinyl) 216-217 840 Me Me 2-F-4-I Br 2-(3-Cl-pyridinyl) 218-219 841 i-Pr H 2-F-4-I Br 2-(3-Cl-pyridinyl) 217-218 842 H H 2,4-di-F Br 2-(3-Cl-pyridinyl) 178-179 843 Me H 2-I-4-F F 2-(3-Cl-pyridinyl) 217-218 844 Me Me 2-I-4-F F 2-(3-Cl-pyridinyl) 238-239 845 H H 2-Me-4-Cl CF₃ 2-(3-F-pyridinyl) * 846 Me H 2-Me-4-Cl CF₃ 2-(3-F-pyridinyl) * 847 Me Me 2-Me-4-Cl CF₃ 2-(3-F-pyridinyl) * 848 i-Pr H 2-Me-4-Cl CF₃ 2-(3-F-pyridinyl) * 849 H H 2,4-di-Cl CF₃ 2-(3-F-pyridinyl) * 850 Me Me 2,4-di-Cl CF₃ 2-(3-F-pyridinyl) * 851 i-Pr H 2,4-di-Cl CF₃ 2-(3-F-pyridinyl) * 852 H H 2,4-di-Cl Br 2-(3-F-pyridinyl) * 853 Me H 2,4-di-Cl Br 2-(3-F-pyridinyl) * 854 Me Me 2,4-di-Cl Br 2-(3-F-pyridinyl) * 855 i-Pr H 2,4-di-Cl Br 2-(3-F-pyridinyl) * 856 H H 2-Me-4-Cl Br 2-(3-F-pyridinyl) * 857 Me H 2-Me-4-Cl Br 2-(3-F-pyridinyl) * 858 Me Me 2-Me-4-Cl Br 2-(3-F-pyridinyl) * 859 i-Pr H 2-Me-4-Cl Br 2-(3-F-pyridinyl) * 860 Me H 2,4-di-Cl CF₃ 5-(1-CH₂CF₃-4-Cl-pyrazolyl) 181-183 R¹, R⁵, and R⁸ are H, except where indicated; B is O, except where indicated. “CN” is bonded through carbon, not nitrogen; for example “CN-Ph” specifies cyanophenyl, not isocyanophenyl *See Index Table B for ¹H NMR data

INDEX TABLE B Compound ¹H NMR Data (CDCl₃ solution unless indicated otherwise)^(a) 191 (DMSO-d₆) δ 1.03 (d, 6H), 2.18 (s, 3H), 3.92 (m, 1H), 7.22-7.30 (m, 2H), 7.35 (m, 1H), 7.62 (dd, 1H), 7.81 (s, 1H), 8.02 (d, 1H), 8.15 (dd, 1H), 8.55 (dd, 1H), 10.34 (s, 1H). 224 (DMSO-d₆) δ 1.01 (d, 6H), 2.16 (s, 3H), 3.92 (m, 1H), 7.27 (m, 2H), 7.35 (m, 1H), 7.89 (s, 1H), 7.96 (m, 1H), 8.37 (s, 2H), 10.42 (s, 1H). 248 (DMSO-d₆)

 1.04 (d, 6H), 4.0 (m, 1H), 7.4 (m, 2H), 7.5 (m, 1H), 7.6 (m 1H), 7.78 (d, 2H), 8.0 (d, 2H), 8.2 (d, 1H), 10.7 (bs, 1H). 249 (DMSO-d₆)

 1.16 (d, 6H), 4.1 (m, 1H), 5.9 (d, 1H), 7.1 (m, 1H), 7.2 (m, 3H), 7.69 (s, 1H), 7.73 (s, 1H), 10.45 (s, 1H). 250 (DMSO-d₆)

 1.0 (d, 6H), 3.9 (m, 1H), 7.4 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 8.0 (d, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 10.6 (s, 1H). 251 (DMSO-d₆)

 1.0 (d, 6H), 4.0 (m, 1H), 7.1 (m, 1H), 7.43 (m, 2H), 7.5 (m, 4H), 7.66 (m, 2H), 10.6 (s, 1H). 254 (DMSO-d₆)

 1.02 (d, 6H), 2.18 (s, 3H), 3.9-4.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.8-7.9 (m, 2H), 8.0 (d, 2H), 8.3 (s, 1H), 10.3 (s, 1H). 255 (DMSO-d₆)

 1.02 (d, 6H), 2.18 (s, 3H), 3.9-4.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.8-7.9 (m, 2H), 8.0 (d, 2H), 8.3 (s, 1H), 10.3 (s, 1H). 256 (DMSO-d₆)

 1.04 (d, 6H), 4.0 (m, 1H), 7.4 (m, 2H), 7.76 (s, 1H), 7.7 (m, 1H), 7.74 (m, 1H), 7.9 (m, 1H), 7.97 (d, 1H), 8.07 (s, 1H), 8.2 (m, 1H), 10.7 (bs, 1H). 271 (DMSO-d₆)

 1.0 (d, 6H), 2.01 (s, 3H), 2.17 (s, 3H), 3.9 (m, 1H), 7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.8-7.9 (s, 1H), 7.9-8.0 (m, 2H), 8.1-8.2 (s, 1H), 10.3-10.4 (s, 1H). 280 (DMSO-d₆)

 1.21 (d, 6H), 2.24 (s, 3H), 4.1-4.3 (m, 1H), 5.9 (d, 1H), 7.02 (d, 1H), 7.1-7.6 (m, 7H), 7.78 (s, 1H), 10.0 (br s, 1H). 281 (DMSO-d₆)

 1.03 (d, 6H), 1.94 (s, 3H), 2.14 (s, 3H), 3.9-4.0 (m, 1H), 7.1-7.4 (m, 8H), 7.8 (s, 1H), 7.9-8.0 (d, 1H), 10.0 (s, 1H). 282 (DMSO-d₆)

 1.04 (d, 6H), 2.18 (s, 3H), 3.9-4.0 (m, 1H), 7.2-7.4 (m, 6H), 7.4-7.6 (m, 2H), 7.9 (s, 1H), 7.9-8.0 (d, 1H), 10.1 (br s, 1H). 285

 1.20 (d, 6H), 2.19 (s, 3H), 4.2 (m, 1H), 5.9-6.0 (d, 1H), 7.1-7.5 (m, 8H), 10.4-10.5 (s, 1H). 321 (DMSO-d₆)

 1.03 (d, 6H), 2.18 (s, 3H), 3.31 (s, 3H), 3.9-4.0 (m, 1H), 7.2-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.81 (s, 1H), 7.9 (d, 1H), 8.0 (br d, 1H), 8.1 (dd, 1H), 8.3 (d, 1H), 10.3 (s, 1H). 405 δ 2.57 (t, 2H), 3.57 (q, 2H), 6.25 (t, 1H), 7.18-7.53 (m, 8H), 9.17 (s, 1H) 406

 1.23 (d, 6H), 4.13 (m, 1H), 5.92 (d, 1H), 7.35 (m, 1H), 7.39 (s, 1H) 7.42 (m, 2H), 7.92 (d, 1H), 8.51 (d, 1H), 10.23 (br s, 1H). 409

 1.13 (d, 6H), 4.15 (m, 1H), 5.99 (d, 1H), 7.40 (m, 1H), 7.41 (m, 1H), 7.63 (m, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.48 (d, 1H), 10.2 (br s, 1H). 495

 1.22 (d, 6H), 2.18 (s, 3H), 4.15 (m, 1H), 4.37 (s, 1H), 5.91 (d, 1H), 7.20 (m, 4H), 7.30 (m, 1H), 7.40 (m, 1H), 7.52 (m, 2H), 7.96 (s, 1H), 10.23 (s, 1H). 496 (DMSO-d₆)

1.05 (d, 6H), 2.15 (s, 3H), 3.74 (s, 2H), 3.93 (m, 1H), 7.26-7.70 (m, 8H), 8.05 (s, 1H), 8.35 (br s, 2H), 10.45 (s, 1H). 511 δ 1.20 (d, 6H), 2.01 (s, 3H), 2.72 (d, 3H), 4.13 (m, 1H), 6.01 (d, 1H), 6.45 (s, 1H), 7.17 (m, 5H), 7.51 (m, 2H), 7.63 (m, 1H), 10.41 (s, 1H). 593 (DMSO-d₆)

 1.04 (d, 6H), 2.32 (s, 3H), 3.91 (m, 1H), 7.44-7.64 (m, 4H), 7.77 (s, 1H), 8.07 (d, 1H), 8.27 (d, 1H), 8.42 (d, 1H), 10.6 (s, 1H). 597 (DMSO-d₆)

 1.03 (d, 6H), 3.88 (m, 1H), 7.65 (dd, 1H), 7.88 (s, 1H), 8.18 (s, 1H), 8.22 (d, 1H), 8.48-8.57 (m, 3H), 10.95 (s, 1H). 599

 1.24 (d, 6H), 4.22 (m, 1H), 5.98 (br d, 1H), 7.30-7.55 (m, 6H), 7.78 (d, 1H), 7.99 (d, 1H), 11.15 (s, 1H). 645

 1.30 (t, 3H), 2.32 (s, 3H), 3.55 (q, 2H), 6.23 (br t, 1H), 7.30 (s, 1H), 7.42 (dd, 1H), 7.91 (d, 1H), 8.20 (apparent s, 2H), 8.52 (d, 1H), 10.92 (s, 1H). 646

 2.21 (s, 3H), 2.90 (s, 3H), 3.12 (s, 3H), 7.42 (m, 2H), 7.92 (d, 1H), 7.92 (d, 1H), 8.00 (d, 1H), 8.50 (d, 1H), 9.92 (br s, 1H). 647 δ 2.32 (s, 3H), 4.02 (t, 2H), 5.18-5.30 (m, 2H), 5.82-5.98 (m, 1H), 7.37 (s, 1H), 7.43 (dd, 1H), 7.50 (br t, 1H), 7.92 (d, 1H), 8.17 (s, 1H), 8.37 (d, 1H), 8.52 (d, 1H), 11.12 (br s, 1H). 648

 0.91 (t, 3H), 1.63 (m, 2H), 2.31 (s, 3H), 3.40 (q, 2H), 6.83 (br t, 1H), 7.35 (s, 1H), 7.42 (dd, 1H), 7.91 (d, 1H), 8.17 (d, 1H), 8.24 (d, 1H), 8.52 (d, 1H), 11.03 (s, 1H). 649

 1.38 (d, 3H), 2.14 (s, 3H), 2.35 (s, 3H), 2.72 (m, 2H), 4.38 (m, 1H), 6.93 (br d, 1H), 7.33 (s, 1H), 7.43 (dd, 1H), 7.91 (d, 1H), 8.18 (d, 1H), 8.28 (d, 1H), 8.52 (d, 1H), 10.93 (s, 1H). 650 (DMSO-d₆)

 2.32 (s, 3H), 2.70 (s, 3H), 7.63 (m, 2H), 7.78 (br s, 1H), 8.18 (br s, 1H), 8.21 (d, 1H), 8.27 (br s, 1H), 8.58 (m, 2H). 651 (DMSO-d₆)

 1.25 (s, 9H), 2.31 (s, 3H), 7.64 (dd, 1H), 7.79 (s, 1H), 8.03 (br s, 2H), 8.22 (d, 1H), 8.28 (s, 1H), 8.54 (d, 1H), 10.62 (s, 1H). 661

 2.33 (s, 3H), 2.75 (br s, 6H), 6.9 (br s, 1H), 7.33 (s, 1H), 7.43 (dd, 1H), 7.91 (d, 1H), 8.19 (br s, 1H), 8.23 (s, 1H), 8.50 (d, 1H), 10.70 (br s, 1H). 742

 1.39 (d, 6H), 2.81 (d, 3H), 4.95 (m, 1H), 6.59 (s, 1H), 6.62 (q, 1H), 7.12 (s, 1H), 7.24 (s, 1H), 7.26 (t, 1H), 7.80 (d, 1H), 8.40 (d, 1H), 9.56 (br s, 1H). 779

 1.24 (d, 6H), 2.22 (s, 3H), 4.20 (m, 1H), 6.10 (d, 1H), 7.35 (s, 1H), 7.44 (t, 1H), 7.55 (s, 2H), 7.87 (s, 1H), 8.48 (d, 1H), 10.7 (s, 1H). 787

 2.91 (d, 3H), 6.3 (m, 1H), 6.77 (d, 1H), 7.3 (obscured, 1H), 7.3-7.4 (m, 2H), 7.8-7.9 (d, 1H), 8.5 (d, 1H), 9.6-9.7 (br s, 1H). 809 (DMSO-d₆)

7.1 (d, 1H), 7.5-7.7 (m, 3H), 7.8 (m, 2H), 8.1-8.2 (d, 1H), 8.5 (d, 1H), 10.5 (br s, 1H). 810 (DMSO-d₆)

 1.03 (d, 6H), 3.9 (m, 1H), 7.1 (d, 1H), 7.4-7.5 (d, 1H), 7.6 (dd, 1H), 7.8 (d, 1H), 8.2 (d, 1H), 8.2 (m, 1H), 8.5 (d, 1H), 10.5 (br s, 1H). 811

 2.78 (s, 3H), 3.04 (s, 3H), 6.9 (d, 1H), 7.1 (d, 1H), 7.29 (d, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9 (d, 1H), 8.5 (d, 1H), 9.8 (br s, 1H). 812

 2.18 (s, 3H), 5.7 (br s, 1H), 6.2 (br s, 1H), 6.7 (d, 1H), 7.3 (m, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9 (d, 1H), 8.4-8.5 (d, 1H), 10.0 (br s, 1H). 813

 1.23 (d, 6H), 2.19 (s, 3H), 4.2 (m, 1H), 5.9 (br s, 1H), 6.7 (d, 1H), 7.21 (d, 1H), 7.26 (obscured, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9 (d, 1H), 8.4-8.5 (d, 1H), 10.1 (br s, 1H). 814

 2.20 (s, 3H), 2.96 (d, 3H), 6.1 (br s, 1H), 6.65 (d, 1H), 7.2 (d, 1H), 7.26 (obscured, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9 (d, 1H), 8.4-8.5 (d, 1H), 10.1 (br s, 1H). 815

 2.06 (s, 3H), 2.78 (s, 3H), 3.08 (s, 3H), 6.9 (d, 1H), 7.0 (s, 1H), 7.1 (s, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9 (d, 1H), 8.4-8.5 (d, 1H), 9.7-9.8 (br s, 1H). 821 (DMSO-d₆)

 2.65 (d, 3H), 7.52 (d, 1H), 7.6-7.8 (m, 2H), 7.9 (d, 1H), 8.0-8.1 (t, 1H), 8.3-8.4 (m, 1H), 8.4 (d, 1H), 10.7 (br s, 1H). 845 (DMSO-d₆)

 2.18 (s, 3H), 7.41 (d, 1H), 7.5 (m, 2H), 7.67 (s, 1H), 7.7 (m, 1H), 7.8 (s, 1H), 8.0-8.1 (t, 1H), 8.4 (d, 1H), 10.4-10.5 (br s, 1H). 846 (DMSO-d₆)

 2.18 (s, 3H), 2.66 (d, 3H), 7.35 (d, 1H), 7.49 (d, 1H), 7.69 (s, 1H), 7.7-7.8 (m, 1H), 8.0-8.1 (t, 1H), 8.3 (m, 1H), 8.4 (d, 1H), 10.4-10.5 (br s, 1H). 847

 2.00 (s, 3H), 2.75 (s, 3H), 3.09 (s, 3H), 6.99 (d, 1H), 7.03 (s, 1H), 7.4-7.5 (m, 1H), 7.5-7.6 (t, 1H), 7.76 (d, 1H), 8.4 (d, 1H), 10.4-10.5 (br s, 1H). 848 (DMSO-d₆)

 1.02 (d, 6H), 2.19 (s, 3H), 3.9 (m, 1H), 7.30 (s, 1H), 7.48 (d, 1H), 7.6-7.8 (m, 2H), 8.0 (t, 1H), 8.1 (d, 1H), 8.4 (d, 1H), 10.4 (br s, 1H). 849 (DMSO-d₆)

 7.56 (d, 1H), 7.6 (s, 1H), 7.7-7.8 (m, 2H), 7.9 (m, 2H), 8.0-8.1 (t, 1H), 8.4 (d, 1H), 10.6-10.7 (br s, 1H). 850

 2.79 (s, 3H), 3.08 (s, 3H), 7.09 (d, 1H), 7.25 (d, 1H), 7.4-7.5 (m, 1H), 7.5-7.6 (t, 1H), 7.78 (s, 1H), 8.4 (d, 1H), 10.5 (br s, 1H). 851 (DMSO-d₆)

1.01 (d, 6H), 3.9 (m, 1H), 7.46 (d, 1H), 7.7 (m, 1H), 7.8 (s, 1H), 7.85 (d, 1H), 8.0 (t, 1H), 8.2-8.3 (d, 1H), 8.4 (d, 1H), 10.6-10.7 (br s, 1H). 852 (DMSO-d₆)

 7.39 (s, 1H), 7.55 (d, 1H), 7.4 (s, 1H), 7.4-7.5 (m, 1H), 7.8 (s, 1H), 7.85 (d, 1H), 8.0 (t, 1H), 8.4 (d, 1H), 10.5 (br s, 1H). 853 (DMSO-d₆)

 2.66 (d, 3H), 7.40 (s, 1H), 7.51 (d, 1H), 7.6-7.7 (m, 1H), 7.84 (d, 1H), 8.0 (t, 1H), 8.3-8.4 (m, 1H), 8.4 (d, 1H), 10.5-10.6 (br s, 1H). 854

 2.80 (s, 3H), 3.07 (s, 3H), 7.10 (s, 1H), 7.31 (d, 1H), 7.35 (s, 1H), 7.4 (m, 1H), 7.5-7.6 (t, 1H), 8.4 (d, 1H), 9.5 (br s, 1H). 855 (DMSO-d₆)

 1.02 (d, 6H), 3.9 (m, 1H), 7.45 (apparent s, 2H), 7.6-7.7 (m, 1H), 7.84 (d, 1H), 7.9-8.0 (t, 1H), 8.2 (d, 1H), 8.36 (d, 1H), 10.5 (br s, 1H). 856 (DMSO-d₆)

 2.17 (s, 3H), 7.33 (s, 1H), 7.4 (d, 1H), 7.5 (m, 2H), 7.6-7.7 (m, 1H), 7.9 (s, 1H), 8.0 (t, 1H), 8.4 (d, 1H), 10.3 (br s, 1H). 857 (DMSO-d₆)

 2.17 (s, 3H), 2.67 (d, 3H), 7.3-7.4 (m, 2H), 7.5 (d, 1H), 7.6-7.7 (m, 1H), 8.0 (t, 1H), 8.2-8.3 (m, 1H), 8.4 (d, 1H), 10.3 (br s, 1H). 858

 2.08 (s, 3H), 2.79 (s, 3H), 3.09 (s, 3H), 6.99 (d, 1H), 7.11 (s, 1H), 7.28 (d, 1H), 7.4 (m, 1H), 7.5-7.6 (t, 1H), 8.3-8.4 (d, 1H), 9.8 (br s, 1H). 859 (DMSO-d₆)

 1.03 (d, 6H), 2.17 (s, 3H), 3.9 (m, 1H), 7.3 (d, 1H), 7.37 (s, 1H), 7.5 (d, 1H), 7.6-7.7 (m, 1H), 7.9-8.0 (t, 1H), 8.1 (d, 1H), 8.3-8.4 (d, 1H), 10.2-10.3 (br s, 1H). ^(a1)H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (br s)-broad singlet.

BIOLOGICAL EXAMPLES OF THE INVENTION Test A

For evaluating control of fall armyworm (Spodoptera frugiperda) the test unit consisted of a small open container with a 4-5-day-old corn (maize) plant inside. This was pre-infested with 10-15 1-day-old larvae on a piece of insect diet by use of a core sampler to remove a plug from a sheet of hardened insect diet having many larvae growing on it and transfer the plug containing larvae and diet to the test unit. The larvae moved onto the test plant as the diet plug dried out.

Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionic surfactant containing alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), unless otherwise indicated. The formulated compounds were applied in 1 mL of liquid through a SUJ2 atomizer nozzle with ⅛ JJ custom body (Spraying Systems Co.) positioned 1.27 cm (0.5 inches) above the top of each test unit. All experimental compounds in this screen were sprayed at 50 ppm and replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 hour and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 25° C. and 70% relative humidity. Plant feeding damage was then visually assessed.

Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 5, 11, 18, 19, 24, 28, 30, 32, 33, 34, 37, 38, 39, 40, 45, 46, 47, 48, 56, 57, 58, 59, 63, 64, 75, 76, 77, 78, 79, 84, 85, 86, 87, 91, 93, 94, 95, 96, 97, 98, 99, 108, 113, 114, 116, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 133, 135, 136, 141, 142, 143, 144, 145, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 160, 161, 164, 165, 166, 168, 169, 170, 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 207, 208, 209, 210, 211, 212, 213, 214, 218, 219, 220, 221, 222, 224, 229, 230, 231, 232, 233, 234, 236, 237, 238, 244, 246, 247, 250, 257, 258, 259, 267, 268, 270, 271, 272, 273, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 287, 288, 289, 290, 291, 292, 293, 294, 295, 297, 298, 299, 300, 301, 302, 305, 306, 307, 309, 313, 314, 315, 316, 319, 320, 321, 322, 324, 325, 326, 327, 328, 329, 330, 335, 336, 338, 339, 341, 344, 345, 346, 347, 348, 349, 351, 352, 356, 364, 365, 366, 367, 370, 371, 372, 373, 374, 376, 377, 384, 387, 388, 390, 391, 392, 393, 394, 395, 396, 401, 402, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 426, 428, 429, 430, 431, 432, 433, 434, 446, 449, 453, 454, 456, 457, 458, 459, 460, 461, 462, 463, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 481, 482, 483, 484, 486, 487, 488, 489, 494, 497, 499, 500, 501, 502, 505, 506, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 611, 612, 613, 615, 616, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 649, 650, 651, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 716, 717, 718, 719, 720, 721, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 759, 762, 763, 766, 767, 768, 769, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 787, 790, 791, 792, 793, 794, 795, 796, 797, 798, 801, 804, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 820, 821, 822, 823, 824, 825, 826, 829, 830, 831, 832 and 833.

Test B

For evaluating control of tobacco budworm (Heliothis virescens) the test unit consisted of a small open container with a 6-7 day old cotton plant inside. This was pre-infested with 8 2-day-old larvae on a piece of insect diet by use of a core sampler as described for Test A.

Test compounds were formulated and sprayed at 50 ppm as described for Test A. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test A.

Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 8, 11, 18, 24, 28, 30, 32, 33, 34, 37, 39, 46, 47, 48, 53, 56, 57, 58, 59, 60, 74, 75, 76, 77, 78, 79, 80, 82, 84, 85, 86, 87, 88, 91, 93, 94, 95, 96, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 141, 142, 143, 145, 147, 150, 151, 153, 154, 155, 156, 158, 160, 161, 164, 165, 166, 168, 169, 170, 171, 174, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 207, 208, 209, 210, 211, 212, 213, 214, 216, 218, 219, 220, 221, 222, 223, 224, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 244, 246, 247, 250, 257, 258, 267, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 304, 305, 306, 307, 309, 313, 314, 315, 316, 319, 320, 321, 322, 324, 325, 326, 327, 328, 336, 338, 339, 341, 345, 346, 348, 353, 356, 357, 364, 366, 367, 370, 371, 372, 373, 374, 377, 381, 383, 384, 385, 387, 388, 390, 391, 392, 393, 394, 395, 397, 399, 401, 402, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 428, 429, 430, 431, 432, 433, 434, 444, 445, 446, 447, 449, 453, 454, 456, 457, 458, 459, 460, 461, 462, 468, 469, 470, 471, 472, 474, 473, 475, 476, 477, 478, 479, 481, 482, 483, 484, 486, 487, 488, 489, 494, 497, 499, 500, 501, 502, 506, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 600, 601, 602, 603, 605, 608, 609, 611, 612, 613, 614, 615, 616, 619, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 649, 650, 651, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 716, 717, 718, 719, 720, 721, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 742, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754 and 755.

Test C

For evaluating control of beet armyworm (Spodoptera exigua) the test unit consisted of a small open container with a 4-5-day-old corn (maize) plant inside. This was pre-infested with 10-15 1-day-old larvae on a piece of insect diet by use of a core sampler as described for Test A.

Test compounds were formulated and sprayed at 50 ppm as described for Test A. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test A.

Of the compounds tested, the following provided excellent levels of plant protection (10% or less feeding damage): 5, 8, 11, 18, 19, 24, 28, 30, 32, 33, 34, 37, 38, 39, 46, 47, 48, 53, 56, 57, 58, 59, 60, 63, 64, 74, 75, 76, 77, 78, 79, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 96, 97, 98, 99, 101, 102, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 133, 135, 136, 137, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 160, 161, 164, 165, 166, 168, 169, 170, 174, 176, 177, 178, 179, 180, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 195, 196, 197, 198, 199, 201, 202, 207, 208, 209, 210, 211, 212, 214, 218, 219, 221, 224, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 244, 246, 247, 250, 257, 258, 267, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 297, 298, 299, 300, 301, 302, 304, 305, 307, 309, 313, 314, 315, 316, 319, 320, 321, 322, 324, 325, 326, 327, 328, 330, 336, 338, 339, 341, 343, 344, 345, 346, 347, 348, 351, 352, 356, 364, 365, 366, 367, 370, 371, 372, 373, 374, 376, 377, 380, 384, 385, 387, 388, 389, 390, 391, 392, 393, 394, 395, 401, 402, 404, 405, 406, 407, 409, 410, 413, 414, 418, 420, 422, 423, 424, 428, 429, 430, 431, 432, 433, 434, 449, 453, 454, 456, 457, 458, 459, 460, 461, 462, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 481, 482, 483, 484, 486, 487, 488, 494, 497, 499, 500, 501, 502, 506, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 532, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 595, 596, 597, 598, 600, 601, 603, 605, 606, 607, 608, 609, 611, 612, 613, 614, 616, 619, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 647, 648, 650, 651, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 669, 671, 672, 673, 674, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 713, 714, 715, 719, 720, 721, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754 and 755.

Test D

For evaluating control of green peach aphid (Myzus persicae) through contact and/or systemic means, the test unit consisted of a small open container with a 12-15-day-old radish plant inside. This was pre-infested by placing on a leaf of the test plant 30-40 insects on a piece of leaf excised from a culture plant (cut-leaf method). The larvae moved onto the test plant as the leaf piece desiccated. After pre-infestation, the soil of the test unit was covered with a layer of sand.

Test compounds were formulated using a solution containing 10% acetone, 90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionic surfactant containing alkylarylpolyoxyethylene, free fatty acids, glycols and isopropanol (Loveland Industries, Inc.), unless otherwise indicated. The formulated compounds were applied in 1 mL of liquid through a SUJ2 atomizer nozzle with ⅛ JJ custom body (Spraying Systems Co.) positioned 1.27 cm (0.5 inches) above the top of each test unit. All experimental compounds in this screen were sprayed at 250 ppm and replicated three times. After spraying of the formulated test compound, each test unit was allowed to dry for 1 hour and then a black, screened cap was placed on top. The test units were held for 6 days in a growth chamber at 19-21° C. and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 283, 297, 370, 371, 372, 388, 431, 434, 469, 470, 472, 473, 474, 476, 479, 486, 494, 497, 499, 500, 501, 502, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 565, 566, 567, 569, 571, 575, 576, 577, 578, 579, 580, 582, 584, 590, 596, 597, 601, 602, 603, 604, 609, 611, 614, 619, 620, 621, 624, 625, 626, 627, 629, 630, 631, 633, 638, 639, 640, 641, 642, 643, 644, 645, 650, 651, 655, 656, 657, 661, 664, 669, 671, 672, 673, 674, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 691, 698, 699, 703, 708, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 771, 776, 779, 780, 781, 783, 784, 787, 793, 809, 810, 811, 812, 821, 822, 823, 824, 825, 826, 830, 831, 832 and 833.

Test E

For evaluating control of cotton melon aphid (Aphis gossypii) through contact and/or systemic means, the test unit consisted of a small open container with a 6-7-day-old cotton plant inside. This was pre-infested with 30-40 insects on a piece of leaf according to the cut-leaf method described for Test D, and the soil of the test unit was covered with a layer of sand.

Test compounds were formulated and sprayed at 250 ppm as described for Test D. The applications were replicated three times. After spraying, the test units were maintained in a growth chamber and then visually rated as described for Test D.

Of the compounds tested, the following resulted in at least 80% mortality: 370, 371, 372, 388, 431, 470, 472, 474, 476, 486, 494, 497, 500, 501, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 566, 567, 568, 575, 576, 577, 578, 579, 582, 596, 601, 602, 603, 604, 609, 611, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 638, 639, 640, 641, 642, 643, 644, 655, 656, 657, 661, 672, 673, 679, 681, 686, 687, 691, 698, 699, 703, 704, 706, 708, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 771, 774, 776, 777, 779, 780, 783, 784, 787, 791, 793, 794, 809, 811, 812, 821, 822, 823, 825 and 826.

Test F

For evaluating control of corn planthopper (Peregrinur maidis) through contact and/or systemic means, the test unit consisted of a small open container with a 3-4 day old corn (main) plant (spike) inside. White sand was added to the top of the soil prior to application. Test compounds were formulated and sprayed at 250 ppm and replicated three limes as described for Test D. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with 10-20 corn planthoppers (18 to 20 day old) nymphs) by sprinkling them onto the sand with a salt shaker. A black, screened cap was placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 19-21° C. and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 370, 371, 372, 388, 431, 469, 470, 472, 474, 476, 486, 489, 494, 497, 500, 501, 506, 512, 514, 515, 516, 517, 518, 520, 530, 531, 532, 533, 534, 536, 537, 538, 539, 540, 542, 543, 544, 546, 548, 549, 550, 551, 553, 554, 555, 557, 559, 560, 561, 562, 563, 564, 566, 567, 568, 575, 576, 577, 578, 579, 582, 596, 601, 602, 603, 604, 609, 611, 620, 621, 624, 625, 626, 627, 628, 629, 630, 631, 638, 639, 640, 641, 642, 643, 644, 655, 656, 657, 661, 672, 673, 679, 681, 686, 687, 691, 698, 699, 703, 704, 706, 708, 709, 710, 711, 719, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 743, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 771, 774, 776, 777, 779, 780, 781, 783, 784, 787, 791, 793, 794, 809, 811, 812, 814, 821, 822, 823, 825 and 826.

Test G

For evaluating control of potato leafhopper (Empoasca fabae Harris) through contact and/or systemic means, the test unit consisted of a small open container with a 5-6 day old Longio bean plant (primary leaves emerged) inside. White sand was added to the top of the soil and one of the primary leaves was excised prior to application. Test compounds were formulated and sprayed at 250 ppm and replicated three times as described for Test D. After spraying, the test units were allowed to dry for 1 hour before they were post-infested with 5 potato leafhoppers (18 to 21 day old) adults). A black, screened cap is placed on the top of the cylinder. The test units were held for 6 days in a growth chamber at 19-21° C. and 50-70% relative humidity. Each test unit was then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 200, 233, 236, 283, 313, 316, 324, 370, 371, 372, 434, 456, 457, 469, 470, 471, 472, 473, 474, 475, 476, 482, 486, 494, 497, 499, 500, 501, 502, 506, 512, 514, 515, 516, 517, 518, 519, 520, 530, 531, 533, 534, 536, 537, 538, 539, 542, 543, 544, 549, 550, 551, 553, 554, 555, 557, 558, 559, 560, 561, 562, 563, 564, 566, 567, 568, 575, 576, 577, 578, 579, 582, 584, 601, 603, 609, 611, 614, 619, 621, 625, 626, 629, 630, 631, 632, 633, 634, 639, 640, 641, 643, 644, 655, 656, 657, 662, 664, 672, 678, 679, 680, 681, 682, 683, 685, 686, 687, 703, 706, 708, 710, 719, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 766, 771, 776, 777, 779, 780, 781, 784, 787, 793, 794, 796, 809, 810, 811, 812, 814, 821, 822, 824, 825, 826, 828, 831, 832 and 833.

Test H

For evaluating control of silverleaf whitefly (Bemisia tabaci), the test unit consisted of a 14-21-day-old cotton plant grown in Redi-earth® media (Scotts Co.) with at least two true leaves infested with 2nd and 3rd instar nymphs on the underside of the leaves.

Test compounds were formulated in no more than 2 mL of acetone and then diluted with water to 25-30 mL. The formulated compounds were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Plants were sprayed to run-off on a turntable sprayer. All experimental compounds in this screen were sprayed at 250 ppm and replicated three times. After spraying of the test compound, the test units were held for 6 days in a growth chamber at 50-60% relative humidity and 28° C. daytime and 24° C. nighttime temperature. Then the leaves were removed and the dead and live nymphs were counted to calculate percent mortality.

Of the compounds tested, the following resulted in at least 80% mortality: 494, 497, 499, 500, 501, 502, 506, 512, 513, 514, 515, 516, 517, 518, 520, 523, 530, 531, 532, 533, 534, 535, 536, 537, 538, 540, 542, 543, 544, 549, 550, 551, 553, 554, 555, 557, 560, 575, 576, 577, 578, 579, 601, 620, 625, 629, 641, 673, 686, 691 and 703.

Test I

For evaluating soil systemic control of tobacco budworm (Heliothis virescens), cotton plants were grown in sassafras soil in 15-cm pots in aluminum trays. When the plants reached square stage (bud formation on the plant) the plants were treated with the test compounds.

Test compounds were formulated in 0.25 mL of acetone and then diluted with water to provide solutions of 10 ppm. Ten mL of the treatment solutions was added to the pots weekly for four weeks, with four replicates of each treatment rate. One day after the second, third and fourth treatments, 35-50 first instar Heliothis virescens larvae were brushed on each plant with paintbrushes and placed on the terminal area, squares, and bolls. Five days after the last infestation with larvae the plants were rated for damage. Of the compounds tested, the following provided excellent levels of plant protection at 10 ppm (10% or less feeding damage) with excellent protection of squares and bolls including no or minimal sepal demage: 214, 283 and 520.

Test J

Test H followed an alternative protocol for evaluating soil systemic control of tobacco budworm (Heliothis virescens). Cotton plants were grown in sassafras soil in 15-cm pots under greenhouse conditions. When the plants reached square stage (bud formation on the plant) the soil surface was treated with the test compounds.

Test compounds were formulated in 0.25 mL of acetone and then diluted with water. Ten mL of treatment solution containing 3 mg of compound was added to the soil surface of each pot. The plants were watered the next day and each day following as needed. At 1, 2 and 4 days after treatment, leaves were excised for evaluation. Two sets of leaves were selected from each plant: upper leaves at approximately second node from terminal and with area greater than 25 cm² and lower leaves at approximately third node from bottom and with area greater than 25 cm². The excised leaves were cut into 3 cm×2 cm sections and placed into test trays made of high-impact styrene consisting of sixteen contiguous wells, each 6 cm wide, 4 cm long and 3 cm deep, with a clear plastic lid molded so that it locked into each well by friction. Solidified agar was placed into the bottom of each well to maintain moisture for plant material. One second instar tobacco budworm was placed into each well with plant material; wells were sealed and held at 25° C. and provided with 16 hours of light per day

Of the compounds tested, the following compounds provided excellent levels of mortality (greater than 70% mortality) on upper leaves excised at 4 days after treatment at the test rate: 497, 530 and 543.

Test K

For evaluating soil systemic control of fall armyworm (Spodoptera frugiperda), corn (maize) plants (Pioneer #3394) were grown in small pots for 5 days until they were at least 4 cm tall and the first leaf was unfurling.

Test compounds were dissolved in 0.25 mL of acetone and diluted with water provide solutions of 1, 10, 50 and 200 ppm. One mL of the test solution was applied by pipette to the surface of the soil in each pot, with eight plants for each compound/rate. The pots were covered and held at 25° C. with 16 hours of light per day. The plants were watered the next day and each day following as needed. After 6 days, the plant matter above the first leaf was excised and cut into 3-cm lengths. Each test unit was a high-impact styrene tray (Supplier: Clearpack Company, 11610 Copenhagen Court, Franklin Park, Ill. 60131) consisting of sixteen contiguous wells each 6 cm wide, 4 cm long and 3 cm deep, with a clear plastic lid molded so that it locks into each well by friction. Solidified agar (2 to 4 mL) was placed onto the bottom of each well to maintain moisture in the wells during the test. Each 3-cm length of corn plant matter was placed into a tray such that the plant matter was contained within two wells. One second-instar fall armyworm (Spodoptera frugiperda) larva was placed in each well, the tray was covered and then the test units were held at 25° C. with 16 hours of light per day. Mortality was observed after four days.

LC₉₀ concentrations (test compound concentrations giving 90% kill of the larvae) were calculated based on probit analysis (log linear regression) using a general linearized model (GLIM) of the SAS statistical computer analysis product of SAS Institute (Cary, N.C., U.S.A.). Of the compounds tested, the following provided excellent levels of mortality, with LC₉₀ values of 10 ppm or less: 200, 202, 313, 494, 497, 500, 513, 515, 516, 518, 520, 531, 533, 535, 538, 542, 543 and 544.

Test L

For evaluating soil systemic control of Colorado potato beetle (Leptinotarsa decemlineata), transplanted tomato plants were grown in 6-cm pots for 5 days until they were at the two true leaf stage.

Test compounds were dissolved in 0.25 mL of acetone and diluted with water provide solutions of 5 ppm. Five mL of the appropriate test solution was applied by pipette to the surface of the soil in each pot, followed by 5 mL of water, with eight plants for each compound/rate. The pots were covered and held at 25° C. with 16 hours of light per day. The plants were watered the next day and each day following as needed. After 4 days, one leaf from each plant was excised and placed into a well of a test tray as described in Test H. One 5-day old Colorado potato beetle (Leptinotarsa decemlineata) was placed in each well, the tray was covered and then the test units were held at 25° C. with 16 hours of light per day. Mortality was observed after four days.

Of the compounds tested, the following provided excellent levels of mortality and feeding inhibition at 5 ppm: 214.

Test M

For evaluating control of boll weevil (Anthonomus g. grandis), samples of the test compounds were dissolved in 1 mL of acetone. This solution was then diluted to 100 mL total volume using an aqueous 500 ppm solution of Ortho X-77™ surfactant. Serial dilutions were made to obtain 50 mL of 50 ppm concentration.

The diluted solutions of the test compounds were sprayed to nm-off on three-week-old cotton plants. The plants were placed on a rotating turntable sprayer (10 rpm). Test solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Sprayed and dried plants were incased in a plastic cylinder. Twenty weevils were placed in each cylinder containing a whole cotton plant. At three days after infestation a feeding damage rating was taken.

Of the compounds tested, the following provided excellent levels of plant protection at 50 ppm (10% or less feeding damage): 530 and 531.

Test N

For evaluating control of thrips (Frankliniella sp.), samples of the test compounds were dissolved in 1 mL of acetone. This solution was then diluted to 100 mL total volume using an aqueous 500 ppm solution of Ortho X-77™ surfactant. Serial dilutions were made to obtain 50 mL of 10 ppm concentration.

The diluted solutions of the test compounds were sprayed to nm-off on three-week-old cotton or soybean plants infested with thrips. The plants were placed on a rotating turntable sprayer (10 rpm). Test solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 kPa). Sprayed and dried plants were incased in a plastic cylinder. At four days after application the total number of dead thrips was recorded.

Of the compounds tested, the following resulted in at least 90% mortality at 10 ppm: 542.

Test O

Test O followed an alternative protocol for evaluating control of Colorado potato beetle (Leptinotarsa decemlineate). Several hours prior to spraying, 5 mg (100% active ingredient, ai) of the test compounds were dissolved in 1 mL of acetone. Using the aqueous solution of 500 ppm of Ortho X-77™, the sample bottle was rinsed and added to the test compounds. This sample solution was then brought to 100 mL with the aqueous solution. Serial dilutions are made to obtain 50 mL of 10 ppm.

Formulated experimental compounds were sprayed to run-off on three week old potato or tomato plants. The plants were placed on a rotating turntable sprayer (10 rpm). Test solutions were applied using a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi (69 KPa). Once the plants were dried, leaves were excised from the treated plant. The leaves were cut, and then the pieces were placed singly into a 5.5 cm-by-3.5 cm cell of a sixteen-well plastic tray. Each cell contained a 2.5 square of moistened chromatography paper to prevent desiccation. One second instar larvae was placed in each cell. At three days after infestation total number of dead Colorado potato beetles was recorded.

Of the compounds tested, the following resulted in at least 90% mortality at 10 ppm: 497, 500, 530, 543, 544, 558, 562 and 684.

Test P

Seventy-eight cotton plants were grown in the greenhouse with natural lighting in Sassafras soil in six inch pots. When six true leaves were on the plant (approximately 36 cm tall) the soil was drenched with a solution of Compound 497, 500, 530, 531 or 543. Each of the 5 compounds was dissolved in 2 mL of acetone, and distilled water was added to make 300 ppm solutions of each of the compounds. The pots were divided into six groups (13 plants/treatment), and 10 mL of each solution was applied over the soil surface of each group with one group left untreated. The plants were arranged in the greenhouse in a randomized block design. Each treatment was divided into three groups for sampling at 24, 48, and 96 hours.

Leaves were taken from the base and terminal of the plants. The leaves from the third node and the terminal leaves greater than 15 cm² were sampled per plant. One clipped leaf from each plant was cut into four pieces and each piece was placed into an well with one second-instar larvae of Heliothis virescens (tobacco budworm). Larval mortality (% M) was recorded 96 hours after sampling. The percentage of leaf feeding (% FF) was also recorded.

Consumption of the leaf in the well was reported as 0-100% (0 equals no feeding). Results are listed in Table P.

TABLE P Percent Larval Mortality and Feeding of Cotton Leaves Over Time 24 h 48 h 96 h Compound Leaf position % M % FF % M % FF % M % FF 497 terminal 29 50 65 50 81 10 base 13 80 46 100 59 20 500 terminal 4 60 38 60 30 30 base 4 80 54 80 30 30 530 terminal 46 50 79 20 96 5 base 33 80 63 50 70 5 531 terminal 25 40 42 40 55 10 base 13 60 33 80 29 10 543 terminal 46 20 63 20 74 5 base 33 30 58 30 17 5 Untreated terminal 0 90 0 90 0 100 base 0 90 0 100 0 95

Test Q

For evaluating german cockroach (Blatella germanica), Compound 531 was mixed with water, and then blended into a slurry with equal amounts (by weight) of peanut butter. The mixture was air dried leaving a peanut butter bait with final concentration of the test substance as indicated in the following table. Approximately 1 gram of bait was placed into each test cage. Ten German cockroaches (Blatella germanica) were then placed into each cage, and provided water via a saturated cotton ball. The cages were held indoors, with indirect sunlight, and temperatures ranging from 22 to 31° C. Four test replicates were set up per rate. Evaluations were conducted 1, 2, 3, 5, and 7 days after treatment (DAT) by counting and removing the killed roaches found in each cage.

TABLE Q German Cockroach Bait Test Average of Killed Cockroaches Rate 1 DAT 2 DAT 3 DAT 5 DAT 7 DAT untreated 0.3 0.3 0.3 1 2  400 ppm 3.8 5.8 6.3 7 7  2000 ppm 6.3 8 8.8 9 9 10000 ppm 9.5 9.5 9.5 9.5 9.5

Test R

For evaluating control of fire ant (Solenopsis xyloni), Compound 531 was mixed with water and then mixed into a slurry with equal amounts (by weight) of Niban granular bait with no active ingredient (supplied by Nisus Corp.). The mixture was air dried, leaving a dry granular bait with final concentration of the test substance as indicated in the following table. The baits were uniformly sprinkled onto the sand substrate in each test cage. Fifty field-collected southern fire ants (Solenopsis xyloni) were then placed into each cage and provided water via a saturated cotton ball. The cages were held indoors with indirect sunlight and temperatures ranging from 22 to 31° C. Four test replicates were set up per rate. Evaluations were conducted at 1, 3, 7, 10, and 14 days after treatment (DAT) by counting and removing the killed ants found in each cage.

TABLE R Fire Ant Bait Test Average of Killed Fire Ants Rate 1 DAT 3 DAT 7 DAT 10 DAT 14 DAT untreated 0.8 1.3 3.5 5.5 8.5   400 ppm 0.5 1.3 40.5 50 50  2,000 ppm 1 2 43 49.8 50 10,000 ppm 0 2.3 42.8 50 50 

1. A method for controlling lepidopteran, homopteran, hemipteran, thysanopteran and coleopteran insect pests, comprising: contacting the insects or their environment with an arthropodicidally effective amount of a compound of Formula I, an N-oxide or an agriculturally suitable salt thereof

wherein A and B are independently O or S; R¹ is H, C₁-C₆ alkyl, C₂-C₆ alkoxycarbonyl or C₂-C₆ alkylcarbonyl; R² is H or C₁-C₆ alkyl; R³ is H; C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₆ cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO₂, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆ trialkylsilyl, phenyl, phenoxy, 5-membered heteroaromatic rings, and 6-membered heteroaromatic rings; each phenyl, phenoxy, 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring optionally substituted with one to three substituents independently selected from the group consisting of C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈ (alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl and C₃-C₆ trialkylsilyl; C₁-C₄ alkoxy; C₁-C₄ alkylamino; C₂-C₈ dialkylamino; C₃-C₆ cycloalkylamino; C₂-C₆ alkoxycarbonyl or C₂-C₆ alkylcarbonyl; R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, CN, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or NO₂; R⁵ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxyalkyl, C₁-C₄ hydroxyalkyl, C(O)R¹⁰, CO₂R¹⁰, C(O)NR¹⁰R¹¹, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, NR¹⁰R¹¹, N(R¹¹)C(O)R¹⁰, N(R¹¹)CO₂R¹⁰ or S(O)_(n)R¹²; R⁶ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, CN, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl or C₃-C₆ halocycloalkyl; or R⁷ is a phenyl ring, a benzyl ring, a 5- or 6-membered heteroaromatic ring, a naphthyl ring system or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R⁹; R⁸ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; each R⁹ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈ (alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R¹⁰ is H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R¹¹ is H or C₁-C₄ alkyl; R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; and n is 0, 1 or 2; wherein the compound of Formula I is included in a composition further comprising an effective amount of at least one additional biologically active compound or agent.
 2. The method of claim 1 wherein A and B are both O; R⁷ is a phenyl ring or a 5- or 6-membered heteroaromatic ring selected from the group consisting of

each ring optionally substituted with one to three substituents independently selected from R⁹; Q is O, S, NH or NR⁹; and W, X, Y and Z are independently N, CH or CR⁹, provided that in J-3 and J-4 at least one of W, X, Y or Z is N.
 3. The method of claim 2 wherein R¹, R² and R⁸ are all H; R³ is C₁-C₄ alkyl optionally substituted with halogen, CN, OCH₃ or S(O)_(p)CH₃; R⁴ group is attached at position 2; R⁴ is CH₃, CF₃, OCF₃, OCHF₂, CN or halogen; R⁵ is H, CH₃ or halogen; R⁶ is CH₃, CF₃ or halogen; R⁷ is phenyl or 2-pyridinyl, each optionally substituted; and p is 0, 1 or
 2. 4. The method of claim 3 wherein R³ is C₁-C₄ alkyl and R⁶ is CF₃.
 5. The method of claim 3 wherein R³ is C₁-C₄ alkyl and R⁶ is Cl or Br.
 6. (canceled)
 7. The method of claim 1 wherein the at least one additional biologically active compound or agent is selected from arthropodicides of the group consisting of pyrethroids, carbamates, neonicotinoids, neuronal sodium channel blockers, insecticidal macrocyclic lactones, γ-aminobutyric acid (GABA) antagonists, insecticidal ureas and juvenile hormone mimics.
 8. The method of claim 1 wherein the at least one additional biologically active compound or agent is selected from the group consisting of abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate, fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine, pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiosultap-sodium, tralomethrin, trichlorfon and triflumuron, aldicarb, oxamyl, fenamiphos, amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben, tebufenpyrad; and biological agents such as Bacillus thuringiensis including ssp. aizawai and kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.
 9. The method of claim 1 wherein the at least one additional biologically active compound or agent is selected from the group consisting of cypermethrin, cyhalothrin, cyfluthrin and beta-cyfluthrin, esfenvalerate, fenvalerate, tralomethrin, fenothicarb, methomyl, oxamyl, thiodicarb, clothianidin, imidacloprid, thiacloprid, indoxacarb, spinosad, abamectin, avermectin, emamectin, endosulfan, ethiprole, fipronil, flufenoxuron, triflumuron, diofenolan, pyriproxyfen, pymetrozine, amitraz, Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin and entomophagous fungi.
 10. The method of claim 1 wherein at least one of the insect pests controlled is selected from the group consisting of Alabama argillacea Hübner (cotton leaf worm), Archips argyrospila Walker (fruit tree leaf roller), A. rosana Linnaeus (European leaf roller) and other Archips species, Chilo suppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambus caliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonella Linnaeus (codling moth), Earias insulana Boisduval (spiny bollworm), Earias vittella Fabricius (spotted bollworm), Helicoverpa armigera Hübner (American bollworm), Helicoverpa zea Boddie (corn earworm), Heliothis virescens Fabricius (tobacco budworm), Herpetogramma licarsisalis Walker (sod webworm), Lobesia botrana Denis & Schiffermüller (grape berry moth), Pectinophora gossypiella Saunders (pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer), Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus (small white butterfly), Plutella xylostella Linnaeus (diamondback moth), Spodoptera exigua Hübner (beet armyworm), Spodoptera litura Fabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperda J. E. Smith (fall armyworm), Trichoplusia ni Hübner (cabbage looper) and Tuta absoluta Meyrick (tomato leafminer), Acyrthisiphon pisum Harris (pea aphid), Aphis craccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid), Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer (apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solani Kaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell (strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheat aphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosoma lanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy (mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid), Metopolophium dirrhodum Walker (cereal aphid), Macrosipum euphorbiae Thomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, green peach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigus spp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (corn leaf aphid), Rhopalosiphum padi Linnaeus (bird cherry-oat aphid), Schizaphis graminum Rondani (greenbug), Sitobion avenae Fabricius (English grain aphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid), and Toxoptera citricida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids); Phylloxera devastatrix Pergande (pecan phylloxera); Bemisia tabaci Gennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes citri Ashmead (citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhouse whitefly); Empoasca fabae Harris (potato leafhopper), Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestes quadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler (green leafhopper), Nephotettix nigropictus Stål (rice leafhopper), Nilaparvata lugens Stål (brown planthopper), Peregrinus maidis Ashmead (corn planthopper), Sogatella furcifera Horvath (white-backed planthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocyba pomaria McAtee white apple leafhopper, Erythroneoura spp. (grape leafhoppers); Magicidada septendecim Linnaeus (periodical cicada); Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotus perniciosus Comstock (San Jose scale); Planococcus citri Risso (citrus mealybug); Pseudococcus spp. (other mealybug complex); Cacopsylla pyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmon psylla), Acrosternum hilare Say (green stink bug), Anasa tristis De Geer (squash bug), Blissus leucopterus leucopterus Say (chinch bug), Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellus Herrich-Schäffer (cotton stainer), Euchistus servus Say (brown stink bug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug), Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezara viridula Linnaeus (southern green stink bug), Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas (large milkweed bug), Pseudatomoscelis seriatus Reuter (cotton fleahopper), Frankliniella occidentalis Pergande (western flower thrip), Scirthothrips citri Moulton (citrus thrip), Sericothrips variabilis Beach (soybean thrip), and Thrips tabaci Lindeman (onion thrip), Leptinotarsa decemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant (Mexican bean beetle) and wireworms of the genera Agriotes, Athous or Limonius).
 11. A benzoxazinone compound of Formula 10

wherein R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, CN, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or NO₂; R⁵ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxyalkyl, C₁-C₄ hydroxyalkyl, C(O)R¹⁰, CO₂R¹⁰, C(O)NR¹⁰R¹¹, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, NR¹⁰R¹¹, N(R¹¹)C(O)R¹⁰, N(R¹¹)CO₂R¹⁰ or S(O)_(n)R¹²; R⁶ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, CN, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl or C₃-C₆ halocycloalkyl; or R⁷ is a phenyl ring, a benzyl ring, a 5- or 6-membered heteroaromatic ring, a naphthyl ring system or an aromatic 8-, 9- or 10-membered fused heterobicyclic ring system, each ring or ring system optionally substituted with one to three substituents independently selected from R⁹; R⁸ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; each R⁹ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈ (alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R¹⁰ is H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R¹¹ is H or C₁-C₄ alkyl; R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; and n is 0, 1 or
 2. 12. The compound of claim 11 wherein R⁷ is a phenyl ring or a 5- or 6-membered heteroaromatic ring selected from the group consisting of

each ring optionally substituted with one to three substituents independently selected from R⁹; Q is O, S, NH or NR⁹; and W, X, Y and Z are independently N, CH or CR⁹, provided that in J-3 and J-4 at least one of W, X, Y or Z is N.
 13. The compound of claim 12 wherein R⁸ is H; R⁴ group is attached at position 2; R⁴ is CH₃, CF₃, OCF₃, OCHF₂, CN or halogen; R⁵ is H, CH₃ or halogen; R⁶ is CH₃, CF₃ or halogen; and R⁷ is phenyl or 2-pyridinyl, each optionally substituted.
 14. The compound of claim 13 wherein R⁶ is CF₃.
 15. The compound of claim 13 wherein R⁶ is Cl or Br.
 16. The compounds of claim 11 wherein R⁴ is at the 2 position and is CH₃, Cl or Br; R⁵ is at the 4 position and is F, Cl, Br, I or CF₃; R⁶ is CF₃, Cl or Br; R⁷ is 3-Cl-2-pyridinyl or 3-Br-2-pyridinyl; and R⁸ is H.
 17. The compound of claim 11 wherein R⁷ is 2-pyridinyl.
 18. The method of claim 1 wherein a plant is contacted by a composition comprising the compound of Formula I, the N-oxide, or the agriculturally suitable salt thereof, applied as a soil drench of a liquid formulation. 